`
`.0)
`
`Europaisches Patentamt
`
`European Patent Office
`Office européen des brevets
`
`© Publication number:
`A
`
`@
`
`EUROPEAN PATENT APPLICATION
`
`6) Application number: 3731093113
`
`@ Int. cm A61K 9/10 , A61l< 47/O0
`
`® Date of filing: 11.12.37
`
`The title of the invention has been amended
`(Guidelines for Examination in the EPO, A—|ll.
`7.3).
`
`Claims for the following Contracting States: ES
`+ GR.
`
`(9 Priority: 18.12.86 <33 8630273
`
`@ Date of publication of application:
`20.07.83 Bulletin 88/29
`
`@ Designated Contracting States:
`AT BE CH DE ES FR GB GR IT LI LU NL SE
`
`
`
`(3 Applicant: T.l.L. Medical Ltd.
`The Old Blue School Lower Square
`lsleworth Mlddlesex TW7 6FlL(GB)
`
`@ Inventor: Story, Michael John
`Elm Cottage Greaves Lane
`Threapwood Near Malpas Cheshire SY14
`6AS(GEl)
`inventor: Flynn, Michael John
`Hunterscombe Dorking Road
`Leatherhead Surrey KT22 8JT(GB)
`
`Representative: Sheard, Andrew Gregory et al
`Kilburn 8: Strode 30, John Street
`London WC1N 2DD(GB)
`
`Micelles containing a non-steroidal antiinflammatory compound.
`
`Non-steroidal anti-inflammatory drugs (NSAIDS) including dicloienac, flufenamlc acid. flUl’blp{0ler‘l. ibuprofen,
`indomethacin. ketoprofen. naproxen. phenylbutazone. piroxicam and sulinclac are administered in micelles to
`alleviate their adverse effects on the gastrointestinal tract. The drugs are formulated with surfactants such as
`polyethoxylated nonionics to give mice-lle-forming compositions.
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`Pharmaceutical Delivery Systems
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`the treatment of
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`inflammatory
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`invention relates to pharmaceutical compositions for use in
`This
`arthropathy.
`inflammatory arthropathy is the general name for a collection of debilitating and painful diseases which
`are extremely common in many countries of
`the world. Their classification is somewhat difficult, but
`inflammatory arthropathy or rheumatic disease seem to be the most common generic terms.
`in this
`specification.
`the term "inflammatory arthropathy“ is used as the preferred generic term. but
`is to be
`understood to include forms of the disease known to some practitioners as rheumatic disease.
`Of the various forms of inflammatory arthropathy, osteoarthrosis (or osteoarthritis) on the one hand and
`rheumatoid arthritis on the other hand are the commonest. Some workers in the field prefer the term
`osteoarthrosis to the term osteoarthritis. although it has been suggested that there is a place for both words.
`It is has been suggested that osteoarthrosis is the most sensible way of labelling the presence of simple
`degenerative joint disease but osteoarthritis separates the acute episodes of an inflammatory nature which
`occur in degenerative joint disease.
`It
`Osteoarthrosis usually has an insidious onset of pain, stiffness and a reduced range of movement.
`commonly effects one or only a small number of joints. Intermittent swelling due to an effusion or an
`inflammatory episode in the affected joint may appear and. later in the disease. a permanent increase in
`size or change of shape may result from bony enlargement. Joint laxity develops with locking and grating.
`it is often the joints which have been used the most or previously effected by trauma or inflammatory
`processes that suffer greatest damage. Thus. the weight-bearing joints of the hips and knees, the lumbar
`spine and the thumb bases (first capometacarpal joints) are common victims of the disease. The latter are
`particularly effected in those who have been manual workers or even keen knitters.
`The essential features of rheumatoid arthritis are pain and swelling of several joints with morning
`stiffness continuing for at least a few weeks. Rheumatoid arthritis tends to affect the peripheral small joints
`symmetrically. Whereas the joints in osteoarthrosis may be described as dry, in rheumatoid arthritis they
`are "juicy". often swollen, hot. tender and red, There may also be accompanying systemic symptoms of a
`general malaise, weight loss, anorexia, mild fever and. on investigation, the finding of a normochromic (or
`hypochromic) normocytic anaemia.
`Other common causes of inflammatory arthropathy include viral arthritis. ankylosing spondylitis, psori-
`atic arthropathy. Reiter's disease. gouty arthritis. septic arthritis (suppurative arthritis). erythema nodosum
`and Henoch-Schoenlein purpura. The most important in the present context are ankylosing spondylitis and
`gouty arthritis.
`Ankylosing spondylitis is characterised by the gradual onset of low—back pain (sometimes bilateral
`buttock pain) with morning stiffness. Peripheral joints may become effected. There is a reduced range of
`spinal movement and chest expansion. Rigidity of the spine follows, often in a cranial direction (first lumbar,
`then dorsal then cervical) with a characteristic clinical picture of high dorsal kyphosis, obliteration of lumbar
`lordosis and flattening of the chest.
`Gouty arthritis is due to the deposition of monosodium urate monohydrate crystals in the joint. Gouty
`arthritis is a very common disease: it is estimated that there are over 300.000 suffers in the United Kingdom
`alone. The popularly held belief that gout is largely due to an over indulgence of port and pheasant is
`40 mainly fallacious. although provocative factors may often be related to its onset. Examples include trauma.
`surgery. unusual physical exercise, severe illness. dietary excess, alcohol and drugs. Any_joint may be
`affected. and the onset may be polyarticular, Affected joints are painful. red. hot. swollen and exquisitely
`tender.
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`The treatment of inflammatory arthropathy has naturally received a fairly large amount of attention from
`pharmacologists and pharmaceutical manufacturers. A first class of drugs that have been used in the
`treatment of inflammatory arthropathy are steroids. Cortisol and its synthetic analogues have the capacity to
`prevent or suppress the development of
`the local heat,
`redness,
`swelling and tenderness by which
`inflammation is recognised. At
`the microscopic level
`they inhibit not only the early phenomena of the
`inflammatory process (oedema, fibrin deposition. capillary dilation. migration of leukocytes into the inflamed
`areas and phagocytic activity) but also the later manifestations (capillary proliferation, fibroblast proliferation,
`deposition of collagen and. still later, cicatrization).
`A
`In clinical terms, the administration of such corticosteroids for their anti-inflammatory effects is palliative
`therapy. The underlying cause of
`the disease remains:
`the inflammatory manifestations are merely
`suppressed. Nevertheless. they are effective in affording symptomatic relief. but prolonged administration of
`corticosteroids may be a very high price to pay for such relief: the adrenal cortex may become atrophied.
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`thereby limiting the body's own ability to survive and adapt in a constantly changing environment. The
`adrenal cortex is the organ of homeostasis: in the absence of the adrenal cortex. survival is possible, but
`only under the most rigidly prescribed conditions.
`In more general terms. it has long been recognised that
`corticosteroids are powerful drugs with slow cumulative toxic effects on many tissues. which may not be
`apparent until made manifest by a catastrophe.
`in the treatment of inflammatory arthropathy. the focus of attention shifted from steroids to a structurally
`unrelated group of compounds known as slow acting anti-rheumatic drugs (SAARDs). SAAFtDs have
`A empirically been categorised into three groups. Group I. including drugs of proven value which are widely
`used. encompasses azathioprine. chloroquine. D~penicillamine and gold salts. Group II relating to clinically
`active drugs under continuing investigation, includes cyciophosphamicie. dapsone, levamisole, methotrexate.
`sulphasalazine,
`thiols and thymopoietin. The group III SAAFlDs are those of less practical or unproven
`treatment: this group includes methylprednisolone pulsing.
`The range of SAARDS is considerable. as has been seen above. and despite much experimental work
`their modes of action are largely unknown. Logistical and toxicity factors prevent the use of SAAFtDs in all
`patients.
`inflammatory arthropathy consists of the non»
`A third category of drugs for use in the treatment of
`steroidal anti-inflammatory drugs (NSAlDs). Aspirin is the prototype NSAID. and for this reason this group of
`drugs is also known as the "aspirin-like" drugs. This secondary nomenclature gives a key to a functional
`similarity of NSAIDs in the absence of any overall chemical similarity: they all appear to owe their anti-
`inflammatory action. at least in part, to the inhibition of prostaglandin synthesis. According to Goodman and
`Gilman in "The Pharmacological Basis of Therapeutics" MacMil|an 7th Edition 1985, it has been established
`in recent years that:
`1. All mammalian cell types studied (with the exception of the erythrocyte) have microsomal enzymes
`for the synthesis of prostaglandins;
`2. Prostaglandins are always released when cells are damaged and have been detected in increased
`concentrations in inflammatory exuclates - all available evidence indicates that cells do not store prostaglan-
`dine. and their release thus depends on biosynthesis d_e @:
`3. All aspirin-like drugs inhibit the biosynthesis and release of prostaglandins in all cells tested: and
`4. With the exception of the anti-inflammatory glycocorticoids. other classes of drugs generally do not
`affect the biosynthesis of prostaglandins.
`NSAlDs (or aspirin-like drugs - the two terms are used interchangeably in this specification) can be
`categorised conveniently into six structural groups. First. there are the salicylic acids and esters including
`aspirin. benorylate. aloxiprin. salsalate and choline magnesium trisalicylate.
`Secondly.
`there are the propionic acid derivatives.
`including ibuprofen. naproxen,
`ketoprofen. fenoprofen. fenbufen. benoxaprofen and suprofen.
`Thirdly. there is the class of oxicams, including piroxicam.
`Fourthly, acetic acid derivatives can be split into two subclasses. Phenylacetic acids include diclofenac
`and fenclofenac: carbo-and heterocyclic acetic acids include indoles such as indomethacin and sulindac
`and pyrroles such as tolmetin.
`Fifthly.
`there are the pyrazolones which include oxyphenbutazone. phenylbutazone. feprazone and
`azapropazone.
`Sixthly, the ienamic acid derivatives include flufenamic acid and meienamic acid.
`NSAlDs have emerged as the drugs of choice in the treatment of inflammatory arthropfithy. This is
`possibly more due to the disadvantages associated with other classes of drugs than in anything else. As
`indicated previously,
`the inflammatory diseases of the joints Cause an extremely high level of discomfort
`and in many instances the results are crippling. The requirement for treatment is unquestioned and the
`treatment is in many cases chronic. that is to say it is continuous as the diseases are generally incurable.
`Unfortunately, the common element in the therapeutic properties of the NSAlDs is also the principle cause
`of side effects. As has been mentioned, the salicylates and other NSAIDS are thought to be effective in
`inflammatory joint disease, and their effectiveness is thought to be partly mediated through prostaglandin
`inhibition. Prostaglandins have been shown to have a protective effect on the gastrointestinal mucosa and.
`therefore. drugs which inhibit their activity are likely to cause gastrointestinal
`intolerance. Drugs with a
`potent
`inhibitory action on prostaglandin synthetase are marketed as having a potent anti-inflammatory
`action but have been shown to cause more faecal blood loss than those with weak anti-prostaglandin
`activity. Aspirin,
`for example, causes as much as an 8-to 10~fold increase in faecal blood loss and
`indomethacin a nearly 3-fold loss. compared with controls. However. when oral prostaglandin E2 lPGE2) at
`doses of 1mg three or four times daily is given with indomethacin or aspirin, the blood loss is reduced to
`control levels without reducing the effectiveness of the drugs.
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`Protection of the stomach from the drug has in some circumstances been shown to be effectively
`achieved by the use of enteric coating, as demonstrated by enlzeric coated aspirin preparations. However.
`the use of conventional enteric coating means that the drug is released in the neutral or slightly alkaline
`environment of the small or large intestine. which Consequently experiences a considerably heightened local
`concentration from direct contact by the drug. intestinal ulceration can occur with chronic administration of
`NSAIDs.
`’
`
`There is therefore a need for an improved and safer form of administration of NSAlDs to give protection
`both in the stomach and in the intestine.
`in addition.
`it would be advantageous to be able to provide a
`means of enhancing the absorption of the NSAlDs. which tend to be poorly water soluble. as well as
`providing an improved concentration of the drug at the cellular level at the site of its action. it is known that
`drugs with a low water solubility have a slow and variable dissolution pattern which can lead to reduced and
`erratic bioavailabilty. in short. what has been needed for some time is a delivery system for NSAlDs which
`protects the gastrointestinal tract from the drug, and which provides a means of alleviating the difficulties
`associated with very poor water solubility.
`The present
`invention is based on the discovery that
`appropriate form of administration of NSAlDs to be achieved.
`According to a first aspect of the present invention.
`there are provided micelles containing a non-
`steroidal anti-inflammatory drug.
`-
`Although NSAlDs themselves tend not to form micelles. amphipathic compounds. known more familiarly
`as surfactants. can form micelles. Surfactants have two distinct regions in their chemical structure. termed
`hydrophilic (water-liking) and hydrophobic (water-hating) regions. Micelles are aggregates in which the
`surfactant molecules are generally arranged in a spheroidal structure with the hydrophobic region at the
`core shielded. in a aqueous solution. from the water by a mantle of outer hydrophilic regions. According to
`a second aspect of the invention."t‘nerefore. there is provided a pharmaceutical composition comprising a
`non—steroidal anti—inflammatory drug and a surfactant. the composition being capable of forming micelles
`containing the non-steroidal anti-inflammatory drug when administered orally.
`it will generally be the case
`that the drug will be dissolved in the surfactant. in its simplest form. the pharmaceutical composition can be
`a solution of the drug in a surfactant. although other components may be present in the system if desired or
`necessary.
`
`the use of micelles enables a particularly
`
`the preparation of an anti-inflammatory
`the invention provides a process for
`in a third aspect.
`composition capable of forming non—steroidal anti-inflammatory drug-containing micelles on oral administra~
`tion to a human or non-human animal. the process comprising admixing a non-steroidal anti-inflammatory
`drug with a surfactant. The process may involve dissolving the drug in the surfactant.
`According to a fourth aspect. the invention provides the use of a non-steroidal anti-inflammatory drug
`and a surfactant in the preparation of a composition for administering the drug in micellar form. insofar as
`the law allows.
`the invention also relates to a method for the treatment or prophylaxis of inflammatory
`arthropathy.
`the method comprising the administration of micelles containing a non-steroidal anti-inflam-
`matory drug.
`r
`Micelles are to be contrasted in terms of their structure with vesicles and with liposomes. Vesicles are
`aggregates of amphipathic molecules arranged in a bilayer. Typically. a vesicle will have a hydrophilic
`interior and a hydrophilic exterior: hydrophilic regions of an internal layer of the molecules will be directed
`inwardly. and hydrophilic regions of an outer layer of the molecule will be directed outwardly. Hydrophobic
`regions of the two layers will be directed towards one another within the molecular wall of the vesicle.
`Liposomes are nothing more than multilamellar vesicles. as is revealed by the fact that
`liposomes
`disintegrate to vesicles upon ultrasonication.
`Surfactants can be variously classified. and often by reference to the nature of the hydrophilic region.
`which can be anionic. cationic, zwitterionic or non-ionic.
`in the present invention. nonionic surfactants are
`preferred. A particularly preferred subcategory of nonionic surfactants are polyoxyethylated surfactants.
`including polyoxyethylated. glycol monoethers, polyoggyethylated fatty acids. polyoxyethylated sorbitan fatty
`esters. and polyoxyethylated castor oils. However. other nonionic surfactants are also particularly appro-
`priate. including sorbitan fatty acid esters, poloxamers. polyethylene glycol fatty acid esters and polyethox-
`ylated glyceryl fatty acid esters.
`‘
`Whatever the precise chemical structure of the surfactant or surfactants used. it is generally preferred
`to use one or more of those that have been already cleared for human ingestion. Therefore. surfactants with
`a low toxicity are preferred. For example. surfactants having an LDso exceeding 10 gkg and preferably 15
`gkg, are generally suitable. The absence of other side effects is of course also appropriate. Although
`surfactants which have already been approved for human ingestion are naturally preferred. the use of other
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`surfactants is not ruled out. not least because they may in time come to be approved for human ingestion.
`The availability of nonionic surfactants is not perceived to be a cause of difficulty. For example. the
`Following surfactants are known to be available.
`
`n = 1-70
`Polyoxyethylene Alky|pheno|sPOE(n) octylphenol
`Triton X series (Ftohm & Haas) lgepal CA series (GAP. USA) Antarox CA series (GAF, UK)
`POE(n)
`nonylphenol n = 1.5-100
`Triton N series (Rhom & Haas) lgepal CO series (GAF, USA) Antarox 00 series (GAF, UK)
`
`None of the polyoxyethylene alkylphenols are as yet approved for human ingestion.
`
`n = 4,23
`
`Polyoxyethylated Glycol MonoethersPOE(n) lauryl ether
`volpo l. series (Croda)
`Brij 30 series (Atlas, ICI Specialties. UK)
`POE(n) cetyl ether
`n = 2,1020
`Brij 50 series(At|as.lCl)
`n = 2.1020
`POE(n) stearyl ether
`Brii 70 and 700 series (Atlas,lCl)
`POE(n) oleyl ether
`n = 2-20
`Volpo N series (Croda)
`Brij 90 series (Atlaslcl)
`POE(n) ceto stearyl ether
`Volpo CS series (Croda)
`
`n = 3-20
`
`20
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`25
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`30
`
`None of these have been approved for internal use, although Cetomacrogol 1000 (Brij 58. Volpo CS20)
`has been extensively used in topical applications.
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`Polyoxyethylated Glyceryl Fay Acid Esters
`
`POE(n) glyceryl monolaurate n = 15.40 Glycerox L series (Croda)
`These products have not been cleared for internal ingestion.
`
`n = 4-100
`
`Polyoxyethylated fiy AcidsPOE(n) monolaurate
`Crodet L series (Croda)
`POE(n) monooleate
`Crcidet 0 series (Croda)
`POE(n) monostearate
`Crodet 8 series (Croda)
`Myri series (Atlas/lC|)
`
`n = 4-100
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`n = 4-100
`
`POE(8) monostearate and POE(40) monostearate appear to be approved for internal ingestion in the UK
`and EEG. and the latter is also approved by the FDA in the US. The other POE(n) monostearates appear
`valid contenders for approval. with the POE(n) monooleates and monolaurates also being likely candidates.
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`Sorbitan _F_a_t1y_ _A_<_:ld_ EstersSorbitan monolaurate
`Grill
`1 (Croda)
`Span 20 (Atlasilcl)
`Sorbitan monopalmitate
`Grill 2 (Croda)
`Span 40 (Atlas.lCl)
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`Sorbitan monostearate
`
`Crill 3 (Croda)
`Span 60 (Atlasylcl)
`Sorbitan trlstearate
`
`Crill 35 (Groda)
`Span 65 (Atlas.|CI)
`Sorbitan monooleate
`
`Grill 4 (Croda)
`Span 80 (At|as:lCl)
`Sorbitan sesquioleale
`Crill 48 (Croda-)
`Sorbitan trioleate
`
`Crill 45 (Croda)
`Span 85 (Atlas.-lCl)
`Sorloitan monoisostearate
`
`Crill 6 (Croda)
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`approval.
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`These surfactants have a similar approval profile to the Sorbitan Fatty Acid Esters. above.
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`Polxoxyethvlated Sorbitan fggv _/§.__c_;l_q EstersPOE(20) sorbltan monolaurate
`Crlllet 1 (Croda)
`‘
`Tween 20 (Atlas.lCl)
`POE(4) sorbitan monolaurate
`Crillet 11 (Croda)
`Tween 21 (Atlas.lCl)
`POE(20) sorbilan monopalmllate
`Crlllet 2 (Croda)
`Tween 40 (Atlasllcl)
`POE(20) sorbltan monostearate
`Crillet 3 (Croda)
`Tween 60 (Atlaelcl)
`POE(4) sorbitan monostearate
`Crlllet 31 (Croda)
`Tween 61 (At|as:|Cl)
`POE(20) sorbitan trlstearate
`Crillet 35 (Croda)
`40 Tween 65 (Atlas.—lCl)
`POE(20) sorbitan monooleate
`Crillet 4 (Croda)
`Tween 80 (Atlas:lC|)
`POE(5) sorbitan monooleate
`Crillet 41 (Croda)
`Tween 81 (AtIas;ICl)
`POE(20) sorbitan trloleate
`Crillet 45 (Croda)
`A
`Tween 85 (Atlasrlcl)
`POE(20) sorbitan monoisostearate
`Crillet 6 (Croda)
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`Polyoxyethylated Castor _(_)_i_l§_POE(n) castor oil
`Elocas Series (Croda)
`Cremophor EL (BASF)
`POE(n) hydrogenated Castor oil
`Croduret series (Croda)
`Cremophor RH40 (BASF)
`
`n = 10-100
`
`n = 10-100
`
`is
`It
`Cremophor EL and Cremophor FlH40 are well established as orally ingestable surfactants.
`envisaged that there would be no problems in registering the Etocas or Corduret series provided BP Castor
`Oil was used in manufacture of the surfactant.
`
`Po|oxamersPOE(n)-POP(m)
`Synperonic PE series(ICl Petrochem & Plastics Div) Pluronic series (Wyandotte Chem. Corp. USA)
`
`Some of these have been used in orally ingested pharmaceuticals. They are of low toxicity.
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`. Polyethylene Glycol Egg/_ fl:_i_g_ EstersPEG(400) distearate
`Cithrol 4DS (Croda)
`PEG(400) monolaurate
`Cithrol 4ML (Croda)
`n = 200300400
`Pl':"G(n) monooleate
`Cithrol MO series (Croda)
`PEG(400) dioleate
`Cithrol 4DO (Croda)
`PEG(n) monostearate
`30 Cithrol MS series (Croda)
`
`n = 400.600 1000
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`There are no toxicology data readily available for these surfactants.
`One factor affecting the choice of surfactant or surfactants to be used is the hydrophilic-lipophilic
`balance (HLB). which gives a numerical indication of the relative affinity of the surfactant for aqueous and
`non aqueous systems. Surfactants having an HLB of about 10 or above. particularly about 12 or above. are
`preferred. However. there may be Cases where a mixture of two or more surfactants provides an improved
`degree of soluloilization over either surfactantused alone.
`In addition to the HLB. the nature of the hydrophobic chain may be taken into account. For example.
`increasing the degree of unsaturation may improve the potential for solubilization. as may increasing the
`chain length anclor having branches. Further a reduction in the molecular weight may give improved
`solubllization on a weight for weight basis, even at the expense of a slight reduction in the HLB.
`It has been
`discovered that it is the provision of the solubilizing interior of the micelles which is important. and this may
`be related to the formation of a solution of the drug in the surfactant prior to the addition of the aqueous
`phase.
`The physical nature of the surfactants will also be a factor to be taken into consideration when choosing
`surfactants for a particular formulation. The choice of surfactant will. among other things. depend on the
`type of formulation. For example. a formulation in the form of a solution may be in the form of a liquid.
`although a solid surfactant may be used in formulating a solution. Soft gelatin capsules may be formulated
`using a surfactant in the form of a liquid, a viscous liquid or melted waxy solid. Hard gelatin capsules may
`be formulated using a liquid. a paste (melted) or a solid (melted) surfactant. There follows below a list of
`potential nonionic surfactants. together with a description of their physical nature and an indication of their
`HLB and LD=,:..
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`Various n0n~steroidal anti-inflammatory drugs in common use today tend to have. as a common
`property. the property of being poorly soluble in water. The poor solubility does nothing to ameliorate the
`problems of their administration in conventional delivery systems. and the present invention provides a
`5 means of overcoming at
`least some of the difficulties associated with poor water solubility. Apart from
`anything else. particles of insoluble drug may tend to lie in folds of the intestinal mucosa, thereby giving
`rise to local irritancy.
`in accordance with the present
`There follows a brief discussion of each of the NSAlDs which are.
`invention. particularly appropriate for being delivered in the form of micelles,
`is
`it
`Diclofenac is sold as the free acid under the trade mark VOLTAROL by Geigy Pharmaceuticals.
`poorly soluble in water but soluble in some organic solvents. Gastrointestinal disturbances have been
`reported in about 7% of all cases. in general, it is fairly well absorbed. but more than 99% of the drug has
`been found to be bound to plasma proteins. The drug has been recommended for use in the treatment of
`rheumatoid arthritis and other rheumatic disorders at a dose of from 75 to 150 mg per day, depending upon
`the form of administration and its frequency. Diclofenac has been supplied as enteric coated tablets, slow
`release tablets. suppositories and in ampoules.
`Flufenamic acid is sold under the trade mark MERALEN by Merrell Dow Pharmaceuticals. Its solubility
`is less than 1 part in 10.000 parts of water. although it is reasonably soluble in various organic solvents. its
`most frequent adverse effects are gastrointestinal disturbances. The drug is well absorbed and is exten-
`sively bound to plasma proteins.
`it is prescribed for rheumatic disorders at doses of from 400 to 600 mg
`per day.
`it is soluble in 100 to
`Flurbiprofen is sold under the trade mark FROBEN by the Boots Company pic.
`1.000 parts of water only, but is readily soluble in most organic solvents. Gastrointestinal side effects have
`been reported in from 23 to 27% of cases. It is readily absorbed. approximately 99% of the drug being
`bound to plasma proteins. it is prescribed for rheumatoid arthritis and other rheumatic disorders and doses
`from 150 to 200 mg per day in a divided dose. The maximum dosage is stated to be 300 mg per day.
`Another Boots Company drug is ibuprofen sold under the trade mark BRUFEN. Other trade marks in
`the UK for ibuprofen are FENBlD and APSIFEN and in the US are RUFEN, ADVIL, MOTRIN and NUPFl|N. It
`is poorly soluble in water: less than 1 part of drug will dissolve in 10,000 parts of water. However, it is fairly
`soluble in simple organic solvents. The most frequent adverse effects reported are. again, gastrointestinal.
`The drug is well absorbed and extensively bound to plasma proteins in give.
`it is prescribed for rheumatic
`arthritis and other musculoskeletal disorders, as well as acute gout. The dosage of the drug is from 600 to
`1200 mg daily in divided doses. with 2.400 mg per day being the maximum.
`-»—
`lndomethacin is sold under the trade mark INDOCID by Thomas Morson Pharmaceuticals. it is also sold
`under the trade mark INBFHLON in the UK and INDOCIN in the US. One part of drug is only soluble in more
`than 10.000 parts of water, but is more soluble in simple organic solvents. The most frequently reported
`adverse effects are gastrointestinal problems, headache and dizziness. The drug is readily absorbed, with
`more than 90% being bound to plasma proteins.
`It
`is prescribed for rheumatoid arthritis. ankylosing
`spondylitis, osteoarthritis and other rheumatic disorders. as well as acute gout. The recommended dosage
`is up to 150 to 200 mg daily in divided doses.
`Ketoproten is sold under the trade mark ORUDIS by May & Baker Limited. who also market controlled
`release pellets of the drug under the trade mark ORUVAIL.
`it is also sold in the UK under the trade mark
`ALFtHEUMAT_ its solubility is less than 1 part in 10.000 parts of water. but it
`is freely soluble in various
`simple organic solvents. The most f