Europaisches Patentamt
`
`European Patent Office
`
`Office european des brevets
`
`@ Publication number:
`
`0 274 870
`A2
`
`EUROPEAN PATENT APPLICATION
`
`0 Application number: 87310931.8
`
`@ Date of filing: 11.12.87
`
`(0 Int. Cl. 4 A61 K 9/10 , A61 K 47/00
`
`The title of the invention has been amended
`(Guidelines for Examination in the EPO. A-111,
`7.3).
`
`6 Applicant: T.J.L. Medical Ltd.
`The Old Blue School Lower Square
`lsleworth Middlesex TW7 6RL(GB)
`
`Claims for the following Contracting States: ES
`+GR.
`
`@ Priority: 18.12.86 GB 8630273
`
`@ Date of publication of application:
`20.07.88 Bulletin 88/29
`
`@ Designated Contracting States:
`AT BE CH DE ES FA GB GR IT L1 LU NL SE
`
`@ Inventor: Story, Michael John
`Elm Cottage Greaves Lane
`Threapwood Near Malpas Cheshire SY14
`6AS(GB)
`Inventor: Flynn, Michael John
`Hunterscombe Dorking Road
`Leatherhead Surrey KT22 8JT(GB)
`
`@) Representative: Sheard, Andrew Gregory et al
`Kilburn & Strode 30, John Street
`London WC1 N 2DD(GB)
`
`@ Micelles containing a non-steroidal antiinflammatory compound.
`
`® Non-steroidal anti-inflammatory drugs (NSAIDs) including diclofenac, flufenamic acid, flurbiprofen. ibuprofen,
`indomethacin. ketoprofen, naproxen. phenylbutazone, piroxicam and sulindac 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 micelle-forming compositions.
`
`\
`\
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`0 274 870
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`Pharmaceutical Delivery Systems
`
`the treatment of inflammatory
`
`s
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`rs
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`20
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`This Invention relates to pharmaceutical compositions for use in
`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
`10 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.
`Osteoarthrosis usually has an insidious onset of pain, stiffness and a reduced range of movement. It
`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
`spme 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
`25 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(cid:173)
`atic arthropathy, Reiter's disease. gouty arthritis. septic arthritis (suppurative arthritis), erythema nodosum
`30 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 indtllgence of port and pheasant is
`40 mainly fallacious. although provocative factors may often be related to its onset. E-xamples 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.
`The treatment of inflammatory arthropathy has naturally received a fairly large amount of attention from
`45 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
`so areas and phagocytic activity) but also the later manifestations (capillary proliferation, fibroblast proliferation,
`deposition of collagen and. still later, cicatrization).
`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 mamfest 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). SAARDs have
`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
`10 active drugs under continuing investigation, includes cyclophosphamide, dapsone. levamisole, methotrexate,
`sulphasalazine, thiols and thymopoietin. The group Ill SAARDs 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 SAARDs in all
`15 patients.
`A third category of drugs for use in the treatment of inflammatory arthropathy consists of the non·
`steroidal anti-inflammatory drugs (NSAIDs). 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" MacMillan 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 exudates • all available evidence indicates that cells do not store prostaglan·
`dins. and their release thus depends on biosynthesis de novo:
`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
`30 affect the biosynthesis of prostaglandins.
`NSAIDs (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 fenamic acid derivatives include flufenamic acid and mefenamic acid.
`NSAIDs have emerged as the drugs of choice in the treatment of inflammatory arthropathy. 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 NSAIDs 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
`mdomethacin a nearly 3-fold loss, compared with controls. However. when oral prostaglandin E2 (PGE2) at
`doses of 1 mg 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.
`
`flurbiprofen,
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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 enteric 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 he1ghtened 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 NSAIDs 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 NSAIDs. which tend to be poorly water soluble, as well as
`ro 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 NSAIDs 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 the use of micelles enables a particularly
`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 NSAIDs 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;-iherefore, there is provided a pharmaceutical composition comprising a
`zs 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.
`In a third aspect. the invention provides a process for the preparation of an anti-inflammatory
`composition capable of forming non-steroidal anti-inflammatory drug-containing micelles on oral administra(cid:173)
`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
`35 and a surfactant in the preparation of a composition for administering the drug in micellar form. Insofar as
`the law allows, the in\l_ention 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(cid:173)
`matory drug.
`Micelles are to be contrasted in terms of their structure with vesicles and with liposomes. Vesicles are
`40 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.
`Uposomes are nothing more than multilamellar vesicles, as is revealed by the fact that liposomes
`.:s 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, polyo!$-yethylated fatty acids. polyoxyethylated sorbitan fatty
`so esters, and polyoxyethylated castor oils. However, other nonionic surfactants are also particularly appro(cid:173)
`priate. mcluding sorbitan fatty acid esters. poloxamers. polyethylene glycol fatty acid esters and polyethox(cid:173)
`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
`55 a low toxicity are preferred. For example. surfactants having an LD5J exceeding 10 g, kg and preferably 15
`g. kg, 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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`surfai::tants IS not ruled out. not least because they may in time come to be approved for human ingestion.
`The availability of nonionic surfactants 1s not perceived to be a cause of difficulty. For example, the
`following surfactants are known to be available.
`
`5
`
`10
`
`n = 1-70
`Polyoxyethylene AlkylphenolsPOE(n) octylphenol
`Triton X series (Rohm & Haas) lgepal CA series (GAF, USA) Antarox CA series (GAF, UK)
`nonylphenol n = 1.5·100
`POE(n)
`Triton N series (Rhom & Haas) lgepal CO series (GAF, USA) Antarox CO series (GAF, UK)
`
`None of the polyoxyethylene alkylphenols are as yet approved for human ingestion.
`
`n = 4,23
`
`15 Polyoxyethylated Glycol MonoethersPOE(n) Iaury! ether
`Volpo L series (Croda)
`Brij 30 series (Atlas.ICI Specialties, UK)
`n = 2,10.20
`POE(n) cetyl ether
`Brij 50 series(Atlas.ICI)
`n = 2.10.20
`20 POE(n) stearyl ether
`Brij 70 and 700 series (Atlas. ICI)
`n = 2-20
`POE(n) oleyl ether
`Volpo N series (Croda)
`Brij 90 series (Atlas ICI)
`25 POE(nl ceto stearyl ether
`Volpo CS series (Croda)
`
`n = 3·20
`
`None of these have been approved for internal use. although Cetomacrogol 1000 (Brij 58, Volpo CS20)
`30 has been extensively used in topical applications.
`
`Polyoxyethylated Glyceryl Fatty Acid Esters
`
`35
`
`POE(n) glyceryl monolaurate n = 15.40 Glycerox L series (Croda)
`These products have not been cleared for internal ingestion.
`
`Polyoxyethylated Fatty AcidsPOE(n) monolaurate
`40 Crodet l series (Croda)
`n = 4-100
`POE(n) monooleate
`Crodet 0 series (Croda)
`n = 4-100
`POE(n) monostearate
`Crodet S series (Croda)
`45 Myrj series (Atlas,ICI)
`
`n = 4-100
`
`POE(8) monostearate and POE(40) monostearate appear to be approved for internal ingestion in the UK
`and EEC, 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.
`
`so
`
`Sorbitan Fatty Acid EstersSorbitan monolaurate
`Crill 1 (Croda)
`55 Span 20 (Atlas. ICI)
`Sorbitan monopalmitate
`Crill 2 (Croda)
`Span 40 (Atlas. ICI)
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`Sorbitan monostearate
`Crill 3 (Croda)
`Span 60 (Atlas. ICI)
`Sorbitan tristearate
`5 Crill 35 (Croda)
`Span 65 (Atlas, ICI)
`Sorbitan monooleate
`Crill 4 (Croda)
`Span 80 (Atlas:ICI)
`ro Sorbitan sesquioleate
`Crill 43 (Croda)
`Sorbitan trioleate
`Crill 45 (Croda)
`Span 85 (Atlas.ICI)
`15 Sorbitan monoisostearate
`Crill 6 (Croda)
`
`The surfactants in this group have good approval rating in the UK. EEC and US. but not complete
`20 approval.
`
`Polyoxyethylated Sorbitan Fatty Acid EstersPOE(20) sorbitan monolaurate
`Crillet 1 (Croda)
`25 Tween 20 (Atlas. ICI)
`POE(4) sorbitan monolaurate
`Crillet 11 (Croda)
`Tween 21 (Atlas.ICI)
`POE(20) sorbitan monopalmitate
`30 Crillet 2 (Croda)
`Tween 40 (Atlas, ICI)
`POE(20) sorbitan monostearate
`Crillet 3 (Croda)
`Tween 60 (Atlas,ICI)
`35 POE(4) sorbitan monostearate
`Crillet 31 (Croda}
`Tween 61 (AtlasiiCI)
`POE(20) sorbitan tristearate
`Crillet 35 (Croda)
`40 Tween 65 (AtlasilCI)
`POE(20) sorbitan monooleate
`Crillet 4 (Croda)
`Tween 80 (AtlasiiCI)
`POE(5) sorbitan monooleate
`45 Crillet 41 (Croda)
`Tween 81 (Atlas;ICI)
`POE(20) sorbitan trioleate
`Crillet 45 (Croda)
`Tween 85 (Atlas!ICI)
`so POE(20) sorbitan monoisostearate
`Crillet 6 (Croda)
`
`These surfactants have a similar approval profile to the Sorbitan Fatty Acid Esters. above.
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`Polyoxyethylated Castor OilsPOE(n) castor oil
`Etocas Series (Croda)
`Cremophor EL (BASF)
`POE(n) hydrogenated castor oil
`s Croduret series (Croda)
`Cremophor RH40 (BASF)
`
`n = 10-100
`
`n = 10-100
`
`Cremophor EL and Cremophor RH40 are well established as orally ingestable surfactants. It is
`10 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.
`
`PoloxamersPOE(n)-POP(m)
`15 Synperonic PE series(ICI Petrochem & Plastics Div) Pluronic series (Wyandotte Chem. Corp. USA)
`
`Some of these have been used in orally ingested pharmaceuticals. They are of low toxicity.
`
`20
`
`. Polyethylene Glycol Fatty Acid EstersPEG(400) distearate
`Cithrol 4DS (Croda)
`PEG(400) monolaurate
`Cithrol 4ML (Croda)
`n = 200.300,400
`25 PEG(n) monooleate
`Cithrol MO series (Croda)
`PEG(400) dioleate
`Cithrol 400 (Croda)
`PEG(n) monostearate
`30 Cithrol MS series (Croda)
`
`n = 400.600 1000
`
`40
`
`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
`35 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 solubilization over either surfactant used 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 and or having branches. Further a reduction in the molecular weight may give improved
`solubilization 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
`<~5 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
`so 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.,J.
`
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`Chemical Identity
`
`Description
`
`HLB
`
`LD50 g/kg
`
`Polyoxyethylated Glycol Monoethers
`
`POE(4)
`POE(23)
`POE(2)
`POE(15)
`POE(20)
`POE(15)
`POE(20)
`POE(2)
`POE(2)
`
`lauryl ether
`lauryl ether
`cetyl ether
`cetostearyl ether
`cetostearyl ether
`oleyl ether
`oleyl ether
`stearyl ether
`oleyl ether
`
`Polyoxyethylated Fatty Acids
`
`OJ
`
`monolaurate
`POE(4)
`monolaurate
`POE(8)
`POE(12) monolaurate
`POE(24) monolaurate
`POE(40) monolaurate
`POE(100) monolaurate
`POE(4)
`monooleate
`POE ( 8) · monooleate
`POE(12) monooleate
`POE(24) monooleate
`POE(40) monooleate
`
`Water white liquid
`Off-white soft solid
`White solid
`Off-white waxy solid
`Off-white hard waxy solid
`Pale straw paste
`Pale straw soft solid
`White solid
`Pale yellow liquid
`
`Pale straw liquid
`White soft solid
`White soft solid
`White waxy solid
`White hard solid
`White hard solid
`Yellow/amber liquid
`Yellow/amber liquid
`Yellow/amber liquid
`Yellow/amber paste/solid
`Yellow soft solid
`
`9.5
`17.0
`5.3
`14.6
`15.6
`14.2
`15.5
`4.9
`4.9
`
`9.3
`12.7
`14.5
`16.8
`17.9
`1 9.1
`7.7
`10.4
`13.4
`15.8
`17.4
`
`9
`9
`22
`?
`3.6
`?
`1 5. 1
`>25
`25
`
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`Metrics EX1022, Page 8
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`
`..,
`
`0
`
`u;
`
`c;
`
`"'
`
`Chemical Identity
`
`Description
`
`(0
`
`POE(100) monooleate
`monostearate
`POE(4)
`POE(8)
`monostearate
`POE(12) monostearate
`POE(20) monostearate
`monos tea rate
`POE(24)
`POE(30) monostearate
`monos tear ate
`POE(40)
`POE( 50) monostearate
`POE(100) monos tear ate
`
`Sorbitan Fatty Acid Esters
`
`Sorbitan monolaurate
`
`Sorbitan monopalmitate
`Sorbitan monostearate
`Sorbitan tristearate
`Sorbitan monooleate
`Sorbitan sesquioleate
`Sorbitan trioleate
`Sorbitan monoisostearate
`
`Yellow waxy solid
`White soft waxy solid
`White waxy solid
`White waxy solid
`White waxy solid
`White waxy solid
`White hard solid
`White hard solid
`White hard solid
`White hard solid
`
`I i Pale yellow viscous
`
`liquid
`Pale tan waxy solid
`Pale tan waxy solid
`Pale tan waxy solid
`Amber viscous liquid
`Amber viscous liquid
`Amber viscous liquid
`Yellow viscous liquid
`
`HLB
`--
`18.8
`7.7
`11 • 1
`13.4
`15 .o
`15.8
`16 .o
`16.9
`17.9
`18.8
`
`8.6
`6.7
`4.7
`2.1
`4.3
`3.7
`1 .8
`4.7
`
`LD50 g/kg
`
`?
`?
`64
`?
`10
`?
`?
`>30
`>25
`25
`
`41
`>16
`31
`> 16
`>40
`?
`>40
`?
`
`0
`1'.)
`
`-...! .,.
`
`co
`-...!
`0
`
`Metrics EX1022, Page 9
`
`

`

`U1
`U1
`
`(J)
`0
`
`-4
`(J)
`
`-4
`0
`
`0
`
`Chemical Identity
`
`Polyoxyethylated Sorbitan Fatty
`Esters
`
`POE(20)
`POE(4)
`POE(20)
`POE(20)
`POE(4)
`POE(20)
`POE(20)
`POE(5)
`POE(20)
`POE(20)
`
`sorbitan monolaurate
`sorbit~n monolaurate
`sorbitan monopalmitate
`sorbitan monostearate
`sorbitan monostearate
`sorbitan tristearate
`sorbitan monooleate
`sorbitan monooleate
`sorbitan trioleate
`sorbitan monoisostearate
`
`Polyoxyethylated Castor Oils
`
`castor oil
`PO~ ( 10)
`castor oil
`POE(35)
`castor oil
`POE(40)
`castor oil
`POE(60)
`POE(100) castor oil
`POE(10
`hydrogenated castor oil
`hydrogenated castor oil
`POE(30)
`hydrogenated castor oil
`POE(40)
`POE{45)
`hydrogenated castor oil
`
`w
`(J)
`
`I
`
`w
`0
`
`F\.)
`(J)
`
`F\.)
`0
`
`o;
`
`'0
`
`(J)
`
`Description
`
`I
`
`HLB
`
`LD50 g/kg
`
`Pale yellow liquid
`Yellow/amber liquid
`Yellow pasty liquid
`Yellow pasty liquid
`Pale yellow waxy solid
`Cream waxy solid
`Yellow/amber liquid
`Yellow/amber liquid
`Yellow/amber liquid
`Yellow liquid
`
`PaLe yellow liquid
`Pale yellow liquid
`Pale yellow liquid
`Pale yellow soft paste
`Pale yellow waxy solid
`Pale straw liquid
`Pale straw liquid
`White soft paste
`White soft paste
`
`16.7
`13.3
`15.6
`14.9
`9.6
`10.5
`15.0
`10.0
`11 • 0
`14.9
`
`6.3
`12.5
`13.0
`14.7
`16.5
`6.3
`11 • 6
`13.0
`14
`
`>39
`>38
`>38
`>38
`>40
`>40
`>38
`>37
`>36
`?
`
`?
`>1 0
`?
`?
`?
`?
`?
`?
`>16
`
`0
`1\.)
`--J
`
`""'
`
`(X)
`--J
`0
`
`Metrics EX1022, Page 10
`
`

`

`<.n
`<.n
`
`"' 0
`
`.. · O'l
`
`.. 0
`
`w
`<.n
`
`w c
`
`1\.J
`U1
`
`"' 0
`
`;;.
`
`c;
`
`V1
`
`Chemical Identity
`
`Description
`
`HLB
`
`LDSO g/kg
`
`hydrogenated castor oil
`POE(60)
`POE(100) hydrogenated castor oil
`
`White soft paste
`White waxy solid
`
`Poloxarners
`
`POE(22) - POP (13)
`POE(90) - POP (13)
`POE(7)
`- POP (17)
`POE(20) - POP (17)
`POE(4)
`- POP (23)
`POE(10) - POP (23)
`POE(27) - POP (23)
`POE(159)- POP (23)
`POE(47) - POP (27)
`POE(6)
`- POP (30)
`POE(51) - POP (30)
`POE(119)- POP (30)
`POE(205)- POP (30)
`POE(19) - POP (37)
`POE(41) -POP (37)
`POE(8)
`- POP (43)
`POE(32) -POP (43)
`POE(296)- POP (43)
`POE(10) - POP (53)
`POE(193)- POP (53)
`
`(L35)
`(F38)
`(L42)
`(L44)
`(L61 )
`(L62)
`(L64)
`(F68)
`(P75)
`(L81)
`(P85)
`(F87)
`(F88)
`(L92)
`(P94)
`(L1 01 )
`(P103)
`(F108)
`(L121)
`(F127)
`
`I
`Liquid
`Solid
`Liquid
`Liquid
`Liquid
`Liquid
`Liquid
`Solid
`Paste
`Liquid
`Paste
`Solid
`Solid
`Liquid
`Paste
`Liquid
`Paste
`Solid
`Liquid
`Solid
`
`14.6
`16.4
`
`18.5
`30.5
`8
`16
`3
`7
`7
`15
`16.5
`2
`1 6
`24
`28
`5.5
`13.5
`1
`9
`27
`0.5
`22
`
`?
`?
`
`0
`1\)
`-...J
`
`..,.
`
`C))
`-...J
`0
`
`Metrics EX1022, Page 11
`
`

`

`0 274 870
`
`12
`
`40
`
`50
`
`t5
`
`20
`
`30
`
`ro
`
`Various non-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
`s 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.
`There follows a brief discussion of each of the NSAlDs which are, in accordance with the present
`invention. particularly appropriate for being delivered in the form of micelles.
`Diclofenac is sold as the free acid under the trade mark VOLT AROL by Geigy Pharmaceuticals. It is
`poorly soluble in water but soluble in some organic solvents. Gastrointestinal disturbances have been
`reported in about 7°'o 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.
`Flurbiprofen is sold under the trade mark FROB EN by the Boots Company pic. lt is soluble in 100 to
`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
`25 bound to plasma proteins. lt 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 FENBID and APSIFEN and in the US are RUFEN, ADVIL. MOTRIN and NUPRIN. 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 ~ vivo. 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.
`Indomethacin is sold under the trade mark INDOCID by Thomas Morson Pharmaceuticals. It is also sold
`35 under the trade mark I