Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1999-06-07
2001-09-11
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S400000, C424S489000, C424S490000, C424S502000, C426S590000
Reexamination Certificate
active
06287592
ABSTRACT:
This invention relates to compositions useful to produce an aqueous drink preparation containing ibuprofen, to said aqueous drink preparations produced therefrom and to a process to prepare said aqueous drink preparations.
Ibuprofen, namely 2-(4-isobutylphenyl)propionic acid is a well known medicament with analgesic, anti-inflammatory and anti-pyretic properties. It is usually sold in the form of racemic ibuprofen (equal amounts of the S(+)-ibuprofen and R(−)-ibuprofen enantiomers). It may also be in the form of the purified form of either enantiomer, especially S(+)-ibuprofen which is acknowledged to be the active form of racemic ibuprofen. Ibuprofen is also available in salt form, for example the sodium or lysine salt of ibuprofen. Ibuprofen is available under prescription (eg Brufen (RTM)), primarily for the treatment of painful and anti-inflammatory disorders including rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, postoperative pain, post-partum pain and soft tissue injuries, generally at doses of up to 3200 mg per day. Ibuprofen is also available as a non-prescription drug (eg Nurofen (RTM)), primarily for the treatment of symptoms of pain and fever including headache, migraine, rheumatic pain, muscular pain, backache, neuralgia, dysmenorrhoea, dental pain and colds and flu, generally at doses up to 1200 mg per day. Compositions containing ibuprofen are usually provided in unit doses to give 200 mg, 400 mg, 600 mg or 800 mg ibuprofen.
It is desired to formulate a composition containing ibuprofen which on the addition of either cold or hot water (preferably hot water) forms an acceptable liquid product for ingestion by the patient. Such products have particular utility in the treatment of pain and the treatment of coughs and colds but may be desired in any therapeutic area where it is convenient to administer the ibuprofen as a drink. The problem is to provide an easily formulated low cost ibuprofen composition which forms a satisfactory drink product solely by the addition of hot or cold water, ie without requiring extra steps to be taken by the patient before or after adding the water to the ibuprofen composition.
Previously it has not been easy to provide compositions containing ibuprofen which, on the addition of hot water, yield satisfactory aqueous drink preparations ready for substantially immediate administration to the patient. One of the problems associated with ibuprofen is that when dissolved, ibuprofen has an unpleasant taste and an undesirable after-burn sensation in the mouth and throat. Although ibuprofen dissolves more readily in water at a pH above 7, an aqueous drink preparation containing ibuprofen with a pH above 7 does not provide an acceptably tasting product unless additional excipients are added to mask the taste. In order to avoid the cost of, and formulation problems associated with the incorporation of taste-masking ingredients in the composition to allow an acceptably tasting drink product, it is therefore desired to keep the ibuprofen undissolved. Accordingly, the ibuprofen composition should be formulated to ensure that on the addition of water thereto the ibuprofen is maintained as a discrete phase separate from the aqueous phase in the aqueous drink preparation.
In addition, it is desired to be able to formulate a product containing ibuprofen which is adapted, on the addition of water at any temperature, to form a satisfactory aqueous drink preparation which is ready for substantially immediate administration to the patient. This includes both addition of cold water and water at a temperature up to and including its boiling point. The formulation of a product containing ibuprofen which is adapted to form an aqueous drink preparation on combination with cold water is advantageous as cold water is readily available from the tap. On the other hand, the formulation of a product containing ibuprofen which is adapted to form an aqueous drink preparation on combination with hot water is advantageous for the treatment of ailments such as coughs and colds where it is desired to administer ibuprofen in the form of a hot drink.
It has been a particular problem to formulate a product containing ibuprofen capable of producing an aqueous drink preparation on combination with water at a temperature above the melting point of ibuprofen. The particular problem that arises with racemic ibuprofen, is that it has a melting point in the range 75-77° C. The melting point of S(+)-ibuprofen is even lower, approximately 55° C. Accordingly, when combined with cold water, the ibuprofen is in solid form whereas when combined with hot water, eg above the melting point of the drug (ie 77° C. for racemic ibuprofen) the ibuprofen is in liquid form. Thus, means must be provided to ensure that not only does the ibuprofen form a discrete solid phase with water at a temperature less than its melting point but that it is capable of forming and holding a satisfactory emulsion on the addition of hot water (>77° C.) whilst the ibuprofen is undergoing the melting process. Furthermore, if hot water is used, it is necessary to hold the ibuprofen as a homogeneous discrete phase evenly distributed throughout the drink over the period in which the drink may be administered to the patient, eg up to 30 minutes. During this period it is likely that the ibuprofen will cool and solidify. It is still required to maintain the ibuprofen as a discrete phase. Thus, an ibuprofen composition is required which, merely by adding water (preferably hot water) is capable of forming a satisfactory aqueous drink preparation containing ibuprofen and in which the ibuprofen can be maintained as a discrete phase when in the solid state or in the liquid state. Furthermore, it is also desired to provide an ibuprofen composition which forms an acceptably tasting aqueous drink preparation substantially immediately on the addition of water, thus avoiding any waiting time and minimising the need for extra steps such as stirring.
Ibuprofen compositions adapted to form drink products on the addition of hot water have previously been proposed. For example WO 93/20850 discloses compositions to which hot water may be added. However, this disclosure requires significant formulation steps to prepare a soluble ibuprofen-beta-cyclodextrin complex which dissolves on the addition of water.
The formation of a dispersion of ibuprofen with cold water has previously been proposed (see European Patent Application Nos. 284167 and 390369). However, the compositions disclosed therein are not adapted to provide satisfactory aqueous preparations on the addition of hot water due to the formation of an oily slick of melted ibuprofen at the surface of the water.
Other proposals have also been made to keep the ibuprofen as a discrete phase in an aqueous preparation. For example, microcapsules, in which NSAID are encapsulated within a polymer wall, are disclosed in WO 95/05166. Although these can be formulated as liquid aqueous suspensions, it does not indicate that it would be suitable to add hot water to these microcapsules. Also such microcapsules require complex preparation steps which the composition of the present invention seeks to avoid. Other means of maintaining ibuprofen as a discrete phase are disclosed in European Patent Application 274870 which discloses that NSAID drugs such as ibuprofen may be formulated with surfactants such as polyethoxylated nonionics or sorbitan fatty acid esters to give micelle-forming compositions. The surfactant is required in considerable excess (ie greater than five times the amount of active ingredient). This is unsatisfactory for a relatively high dose drug such as ibuprofen (eg 100-400 mg doses) due to the large amount of surfactant required.
The formation of liposomes using phospholipid materials has been proposed in which a drug is encapsulated in a liposome (a lipid bilayer membrane) in an aqueous formulation. See for example European Patent Application 622072 which discloses the formation of liposomes based on yolk lecithin and soybean lecithin as lip
Arent Fox Kinter Plotkin & Kahn PLLC
Rose Shep K.
The Boots Company PLC
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