Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1993-10-26
2003-02-25
Barts, Samuel (Department: 1206)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06525214
ABSTRACT:
This invention relates to a salt of S(+)-ibuprofen, to its anti-inflammatory, anti-pyretic and analgesic activity, to pharmaceutical compositions containing the salt, to its use as an intermediate in a process to prepare S(+)-ibuprofen of high enantiomeric purity and to a novel form of the salt.
(±)-2-(4-Isobutylphenyl)propionic acid, ibuprofen, is a potent and well tolerated anti-inflammatory, analgesic and anti-pyretic compound. The racemic mixture consists of two enantiomers, namely S(+)-2-(4-isobutylphenyl)propionic acid or S(+)-ibuprofen and R(−)-2-(4-isobutylphenyl)propionic acid or R(−)-ibuprofen. It is known that S(+)-ibuprofen is the active agent and that R(−)-ibuprofen is partially converted into S(+)-ibuprofen in humans. The drug has been previously marketed as the racemic mixture, however, in certain circumstances it may be advantageous to administer S(+)-ibuprofen. Problems arise, however, when attempting to formulate S(+)-ibuprofen into pharmaceutical compositions due to its low melting point of 51° C.
DE 3922441 considers the formulation problems associated with the low melting point of S(+)-ibuprofen and proposes a solution to the problem by using the calcium salt of S(+)-ibuprofen on its own or in admixture with a compound selected from the group comprising the sodium-, potassium- or ammonium- S(+)-ibuprofen salt, ibuprofen or S-(+)-ibuprofen. It is disclosed that the pharmaceutical composition must contain the calcium salt as an essential component as alkali metal salts of S(+)-ibuprofen per se, for example the sodium salt, are too hygroscopic to allow satisfactory tabletting.
We have now prepared and characterised the sodium salt of S(+)-ibuprofen and surprisingly we have found that it possesses advantageous formulation properties. The sodium salt of S(+)-ibuprofen has a negative optical rotation of −4.3° and is thus correctly named as S(−)sodium 2-(4-isobutylphenyl)propionate.
The preparation of the sodium salt of S(+)-ibuprofen in anhydrous form for use as a base, as an alternative to the use of pyridine, in a process to racemise S(+)-ibuprofen, is described in U.S. Pat. No. 4,946,997. In this reference no details are given of the physical properties of the material obtained and there is no suggestion that the material is suitable for pharmaceutical use.
The administration of S(+)-ibuprofen as a solution in dilute sodium hydroxide to a normal subject in a volunteer study has been reported (Lee et al, J. Pharm Sci. Vol. 73, No. 11, 1984, pp 1542-44). However, the taste of such a preparation would be unacceptable to the vast majority of patients.
The present invention provides pharmaceutical compositions comprising S(−)sodium 2-(4-isobutylphenyl)propionate having an enantiomeric purity of at least 90%, together with a pharmaceutically acceptable carrier, with the exception of (a) compositions consisting of a solution of S(−)sodium 2-(4-isobutylphenyl)propionate in water with no additional pharmaceutical excipient and (b) compositions comprising the calcium salt of S(+)-ibuprofen.
S(−)sodium 2-(4-isobutylphenyl)propionate possesses a number of formulation advantages over S(+)-ibuprofen. S(−)sodium 2-(4-isobutylphenyl)propionate may be easily compressed into tablets even on long compressing runs during which the temperature of the tablet tooling will rise. Under similar circumstances S(+)-ibuprofen would tend to stick and generally display poor flow characteristics. S(−)sodium 2-(4-isobutylphenyl)-propionate may also be easily milled to the most appropriate particle size. These advantages would not be expected from consideration of the prior art (DE 3922441) referred to earlier.
The high melting point of S(−)sodium 2-(4-isobutylphenyl)propionate, 220-222° C., allows higher temperatures to be used in drying intermediates in formulation processes, for example granules, compared to the corresponding intermediates containing S(+)-ibuprofen. The high melting point also gives increased physical stability to final formulations containing S(−)sodium 2-(4-isobutylphenyl)propionate during storage for example in hot climates compared to final formulations containing S(+)-ibuprofen which may deteriorate when stored at temperatures close to the melting point of S(+)-ibuprofen.
S(−)sodium 2-(4-isobutylphenyl)propionate has a higher water solubility than S(+)-ibuprofen and is thus very useful in the formulation of pharmaceutical compositions containing water. Such compositions may be formulated to have a bright, clear, aesthetically-appealing appearance.
An additional formulation advantage is that S(−)sodium 2-(4-isobutylphenyl)propionate will resist esterification with excipients which contain a hydroxyl group for example mono-, di-, tri- or poly-hydric alcohols. For example this is a problem encountered when formulating S(+)-ibuprofen with liquid fill excipients, for example, esterified natural vegetable oils which may contain alcohols.
The enantiomeric purity of S(−)sodium 2-(4-isobutylphenyl)propionate used in the pharmaceutical compositions of the invention is in the range of 90-100%. Preferably the enantiomeric purity of the S(−)sodium 2-(4-isobutylphenyl)propionate used greater than 95%, more preferably the enantiomeric purity is greater than 98% and most preferably the enantiomeric purity is greater than 99%. In an especially preferred embodiment of the present invention the enantiomeric purity is greater than 99.5% e.g. greater than 99.9%. We have found that S(−)sodium 1-(4-isobutylphenyl)-propionate can exist in the form of a stable dihydrate which is a novel and valuable compound for use in preparing pharmaceutical compositions. In the following detailed description of compositions of the invention the term S(−)sodium 2-(4-isobutylphenyl)propionate includes the anhydrous form and hydrated forms. Preferably the dihydrate is used.
S(−)sodium 2-(4-isobutylphenyl)propionate dihydrate may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
In therapeutic use, S(−)sodium 2-(4-isobutylphenyl)propionate may be administered orally, rectally, parenterally or topically, preferably orally or topically. Suitably the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 1-99% by weight of S(−)sodium 2-(4-isobutylphenyl)propionate. The compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of S(−)sodium 2-(4-isobutylphenyl)propionate is in the range of 10-1200 mg in a precalculated amount to provide doses which are equivalent by weight to doses of for example 100 mg, 200 mg, 400 mg or 800 mg of S(+)-ibuprofen.
Solid compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets and capsules. Suitably tablets may be prepared by mixing S(−)sodium 2-(4-isobutylphenyl)-propionate with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing S(−)sodium 2-(4-isobutylphenyl)-propionate with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets may be formulated in a manner know
Armitage Bernard John
Coe Paul Frederick
Arent Fox Kintner & Plotkin & Kahn, PLLC
Barts Samuel
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