Patent Application
20130059805
This invention relates to a macrolide composition. More particularly this invention relates to a novel amorphous form, of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside or azithromycin. This invention further relates to a preparation method of a medicament. More particularly this invention relates to a method of increasing the solubility of azithromycin.
Azithromycin is an azalide and a member of the macrolide family of antibiotics. This 15-membered-ring, macrolide antibiotic, is very similar in composition, chemical structure (semi-synthetic) and mechanism of action to erythromycin. Polymorphs of azithromycin commonly present as anhydrous (MM=749.00 g/mol), monohydrate (MM=767.02 g/mol) or dihydrate (MM=785.02 g/mol) azithromycin. It should however be noted that azithromycin is acid-stable in 0.1 N HCl and that the dihydrate is currently the most stable polymorphic form.
The chemical formula for azithromycin dihydrate is C38H72N2O12.2H2O and the chemical structure of anhydrous azithromycin differs from erythromycin through methyl-substitution of a nitrogen atom in the lactone ring.
The preparation of some amorphous forms of azithromycin has previously been described in U.S. Pat. Nos. 6,245,903 and 6,451,990.
U.S. Pat. No. 6,245,903 describes an anhydrous form of azithromycin and further provides a method to purify an amorphous anhydrous azithromycin form using a chromatographic procedure or by using a solvent evaporation method.
U.S. Pat. No. 6,451,990 describes a non-crystalline form of azithromycin which includes the preparation method of forming a solution of azithromycin and an aliphatic alcohol or cyclic ethers and lyophilising said solution.
All non-crystalline forms of azithromycin referred to above are manufactured using solvents and/or lyophilisation. Although the aforesaid methods are well-known in the pharmaceutical industry for the preparation of different forms of a drug there are several disadvantages with these known methods. Some of the disadvantages are that the methods are time-consuming and require reagents for manufacturing. Yet a further disadvantage associated with these methods is that the solvents in the structure of the non-crystalline azithromycin can influence the physico-chemical properties of azithromycin.
Azithromycin has an anti-bacterial spectrum parallel to erythromycin's spectrum. It is however more effective against Haemophilus influenzae and other gram-negative bacteria, including Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcus pyogenes; Haemophilus ducreyi; Moraxella catarrhalis; Neisseria gonorrhoeae; Chlamydia pneumoniae; Chlamydia trachomatis; Mycoplasma pneumoniae; Helicobacter pylori; Salmonella typhi; and Mycobacterium avium intracellulare.
A disadvantage associated with known commercially available azithromycin dihydrate (raw material) is that it is poorly soluble in water.
A further disadvantage associated with azithromycin is that its poor water-solubility influences other pharmacokinetic properties resulting in the poor bioavailability (only 38% of an orally administered dose reaches systemic circulation) of the active drug.
Yet another disadvantage of azithromycin is that said poor bioavailability necessitates the administration of relatively large quantities of azithromycin in order to achieve the desired therapeutic effect.
A disadvantage associated with the use of relatively large quantities of azithromycin is that there is a potential increase in the side-effects associated with this active ingredient, in turn leading to poor patient compliance and potentially resulting in bacterial drug-resistance.
An even further disadvantage associated with the use of relative large quantities of azithromycin is that there is an increase in the production and manufacturing cost of the product, thereby increasing the cost of treatment.
An object of the present invention is to provide a stable novel form of azithromycin. Another object of the invention is to provide a method for increasing the solubility of azithromycin. Yet another object of the invention is to provide a medicament prepared in accordance with such a method with which the aforesaid disadvantages may be overcome or at least minimised.
According to a first aspect of the invention there is provided a composition comprising a stable amorphous non-crystalline glass form (Form-II) of azithromycin.
The amorphous non-crystalline glass form (Form-II) of azithromycin may display an infra-red pattern having a relatively broad peak at approximately 3500 and 1727 cm−1 and at least one characteristic peak at approximately 2970 and 2938 cm−1. The infra-red pattern may be substantially depicted as in
The amorphous non-crystalline glass form (Form-II) of azithromycin may display a differential scanning calorimetry thermogram substantially as depicted in
The amorphous non-crystalline glass form (Form-II) of azithromycin may have at least 50%, preferably at least 150%, increased solubility relative to anhydrous, monohydrated or dihydrated azithromycin in water.
The amorphous non-crystalline glass form (Form-II) of azithromycin may have at least 5%, preferably at least 10%, increased solubility relative to anhydrous, monohydrated or dihydrated azithromycin in 0.1 N hydrochloric acid (pH 1).
The amorphous non-crystalline glass form (Form-II) of azithromycin may have at least 10%, preferably at least 20%, increased solubility relative to anhydrous, monohydrated or dihydrated azithromycin in phosphate buffer (pH 6.8).
According to a second aspect of the invention there is provided a method of increasing the solubility of azithromycin including the steps of:
The step of elevating the temperature of the azithromycin to above its melting point includes the step of elevating the temperature thereof to between 100 and 140 degrees Celsius, preferably 130 degrees Celsius, in the absence of a solvent.
The temperature of the selected azithromycin is elevated to above its melting point in the absence of a solvent.
According to a third aspect of the invention there is provided a medicament prepared from anhydrous, monohydrated or dihydrated azithromycin in accordance with the method of the second aspect of the invention.
According to a fourth aspect of the invention there is provided use of a pharmaceutically effective amount of an amorphous non-crystalline glass form (Form-II) of azithromycin in accordance with the first aspect of the invention and prepared in accordance with the method of the second aspect of the invention in a method of treating a patient suffering from bacterial infections.
According to a fifth aspect of the invention there is provided use of a pharmaceutically effective amount of an amorphous non-crystalline glass form in accordance with the first aspect of the invention and prepared in accordance with the method of the second aspect of the invention in a method of preparing a medicament for use in treating a patient suffering from bacterial infections.
According to a sixth aspect of the invention there is provided a method of treating a patient suffering from bacterial infections including the step of administering to such a patient a pharmaceutically effective amount of an amorphous non-crystalline glass form (Form-II) of azithromycin in accordance with the first aspect of the invention and prepared in accordance with the method of the second aspect of the invention.
According to yet another aspect of the invention there is provided a medicament prepared from amorphous non-crystalline glass form (Form-II) of azithromycin in accordance with the method of the second aspect of the invention, together with at least one inert pharmaceutically acceptable carrier or diluents in the dosage form selected from the group consisting of tablets; capsules; powders; solutions; syrups; suspensions; bolus injection; continuous infusion; powder for reconstitution; enemas; douche; pessary; transdermal patch; dermal patch; ointments; creams; gels; lotions; sprays and lozenges.
The invention will now be described further, by way of example only, with reference to the accompanying drawings wherein:
According to a preferred embodiment of the invention there is provided a method for increasing the solubility of azithromycin, by providing a stable amorphous non-crystalline glass form (Form-II) of azithromycin.
The method includes the steps of selecting azithromycin from the group consisting of anhydrous, monohydrated or dihydrated azithromycin; elevating the temperature of the azithromycin to above the melting point thereof; and reducing the temperature of the melt sufficiently to allow it to set into an amorphous non-crystalline glass form (Form-II) of azithromycin having relatively increased solubility.
The first step of the method, according to a preferred embodiment of the invention is to select azithromycin raw material from known commercially available anhydrous, monohydrate or dihydrated form.
The following step of the method is to place the azithromycin raw material in a suitable container, in the absence of any solvents, and heat it to approximately 130 degrees Celsius in a dry heat oven and afterwards cooling the melt to room temperature (25 degrees Celsius).
Alternatively, the azithromycin raw material can be placed in a suitable container and heated in any suitable environment to approximately 130 degrees Celsius. The melt is then cooled to room temperature (25 degrees Celsius).
It has surprisingly been found that the amorphous non-crystalline glass form (Form-II) of azithromycin is structurally stable and significantly more soluble in water, phosphate buffer and 0.1 N hydrochloric acid compared to conventional anhydrous, monohydrate or dihydrated azithromycin prepared according to prior art methods.
In further analysis of the amorphous non-crystalline glass form (Form-II) of azithromycin, each of five replicate test tubes were filled with an excess of amorphous non-crystalline glass form (Form-II) of azithromycin and 10 ml of solubility medium. The process was performed with each of the following mediums: 0.1 N hydrochloric acid (pH 1), acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and distilled water. This method was also used for testing the prior art azithromycin dihydrate.
The test tubes were then fixed to a rotating axis (54 rpm) and submerged in a water bath at 37 degrees Celsius±2 degrees Celsius for twenty-four hours. The contents of the test tubes were filtered through a 0.45 μm filter and the respective filtrates were subsequently diluted.
The concentrations of the filtrates were determined by HPLC (high performance liquid chromatography) assay. The HPLC assay was performed utilising a mobile phase (600:400) consisting of 8.7 g/L potassium dihydrogen phosphate buffer (pH 4.5) and acetonitrile. A Luna C18 250 mm×4.6 mm column was used with a flow rate of 0.5 mL/min and a wavelength of 210 nm. Validation of this method provided a linear regression r2 of 0.9999.
Referring to
Referring to
The most distinguishing difference between the IR patterns of the raw material (
The IR pattern of azithromycin dihydrate (
The IR-pattern of the raw material (
The applicant established that amorphous non-crystalline glass form (Form-II) of azithromycin is structurally stable (at 40° C. and 75% relative humidity) over a period of time and remained amorphous as shown in the XRPD pattern (
Referring to
The stability tests indicate that the amorphous non-crystalline glass form (Form-II) of azithromycin remained structurally stable as an amorphous non-crystalline form.
The thermogravimetric analysis (TGA) trace of
Amorphous non-crystalline glass form (Form-II) of azithromycin is formulated for administration in any convenient way and the invention includes within its scope pharmaceutical compositions comprising amorphous non-crystalline glass form (Form-II) of azithromycin adapted for use in human or veterinary medicine.
The pharmaceutical compositions are presented for use in a conventional manner with the aid of a pharmaceutically acceptable carrier or excipient and may also contain, if required, other active ingredients. The amorphous non-crystalline glass form (Form-II) of azithromycin is typically formulated for oral, buccal, topical or parenteral administration.
Oral administration is the preferred dosage form, particularly in the form of tablets and capsules. The pharmaceutical composition for oral administration conveniently takes the form of tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. Buccal administration compositions take the form of tablets or lozenges formulated in conventional manner.
The amorphous non-crystalline glass form (Form-II) of azithromycin is further formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection are presented in unit dosage forms in ampoules, or in multi-dose containers, with an added preservative. The compositions further take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient is in powder form for reconstitution with a suitable vehicle.
The amorphous non-crystalline glass form (Form-II) of azithromycin is yet further formulated in topical applications, comprising ointments, creams, gels, lotions, powders; transdermal patches, dermal patches or sprays prepared in a conventional manner.
The particulate unsolvated anhydrous form of nevirapine (Form-I) is yet further formulated in rectal and vaginal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.
For oral administration a convenient daily dosage regime of amorphous non-crystalline glass form (Form-II) of azithromycin is a total of 200 mg to 500 mg per day for three days, dependent upon the age and condition of the patient.
The amorphous non-crystalline glass form (Form-II) of azithromycin prepared in accordance with the method of the present invention is formulated into a medicament and used in a method of treating a patient suffering from a bacterial infection by administering to such a patient a pharmaceutically effective amount thereof of a total of 200 mg to 500 mg per day for three days, dependent upon the age and condition of the patient.
It will be appreciated that the disadvantages associated with prior art forms of azithromycin, namely anhydrous, monohydrate of dihydrate forms, could be alleviated with the method according to the invention. In particular, the bioavailability of azithromycin could be increased as a result of the increased solubility of amorphous non-crystalline glass form (Form-II) of azithromycin. Moreover, reduced quantities of amorphous non-crystalline glass form (Form-II) of azithromycin would be required in use in treating patients suffering from bacterial infections, resulting not only in reduced risk to side-effects but to a reduced cost in treatment. Yet further, the advantages associated with the preparation of Form-II is done in the absence of any solvent, this being more cost-effective and less time consuming than known prior art methods.
Applicant thus foresees that amorphous non-crystalline glass form (Form-II) of azithromycin would not only present a relatively cheaper alternative to conventional production and manufacturing methods, but would also present a product that is superior in solubility to conventional anhydrous, monohydrate or dihydrate forms of azithromycin.
It will be appreciated further that variations in detail are possible with a method for preparing a medicament and a medicament prepared with such a method, according to the invention without departing from the scope of this disclosure.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2009/09098 | Dec 2009 | ZA | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB2010/055842 | 12/15/2010 | WO | 00 | 11/5/2012 |
