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`British Pharmacopoeia 1998
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`Volume II
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`Published on the r<=.,E:o:r1n;endaAtionM_<)f,r_:I_1’_t=:;,j_' _ __
`Medicines Commission pursuant tdtile -_
`—.
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`Medicines Act 1968 ‘and notified in drafnfto
`the "European Cbmmiéion in a'ccordénéef
`with Directive '83/18.9/EEC (as aré11e1_1'd’ed.)A
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`_*'
`” 7
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`1
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`London: The Stationery Office
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`SENJU-MITSUBISHI 2094
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`
`MENT OF HEALTH
`DEPART
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`SCOTTISH OFFICE
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`© Crown copyright 1998
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`Published by The
`for the Department
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`Stéuionéry Ofiice und
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`of I-Ieaith on behalf‘
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`duction should lee ma
`Applications for repro
`2-16 Colegate, Norwich, NIB IBQ
`St. Clements House,
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`2.
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`ISBN 0 11 322100
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`British Pharmacopoeia Commission
`
`Office:
`Market Towers
`1 Nine Elms Lane
`London SW8 SNQ
`hone: +44 (0)171 273 0561
`Telep
`)1'71 273 0566
`Facsimile: +44 (0
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`Laboratory:
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`Government Buildings
`Block 2, Honeypot Lane
`Stanmore
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`1AY
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`Facsimile: +44
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`Limited under the authority
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`Stationery Ofliee
`Offiee and the Queen’.-:
`the United Kingdom by The
`Stationery
`Printed in
`the Controller of Her Maiestfs
`superintendenee of
`Acts of Parliament
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`and
`Printer of
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`

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`14:28
`__
`1:
`ir* *1-
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`ii
`if
`‘I’-g,-‘Ir
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`
`EYE PREPARATIONS '
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`solvent used for the preparation,
`—- the content of active principle andlor the ratio of -
`starting rnate::iaL to final soft extract,
`— the name and concentration of any ‘added antimicrobial
`preservative,
`
`Dry Extracts
`DEFINITION
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`Eye Preparations comply-ruizft the reqm‘re'ments_ ofthe
`ed:'o'on~ qf the European Pharmacopoeia [1'163]. These 'requ_i1_fe-
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`moms are reproduced after zhe"heada'ng ‘Definition’ below,
`PhEur
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`DEFINITION
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`Dry extracts are solid preparations obtained by evapor~
`. ation.of:'-the solvent _used for their production." Dry extracts
`=-generally-haveaa dry residue of.not,less'than 95 per cent-by
`ma-s_s.. Suitable inert materials may be added.
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`Standardised dryextracts are adjusted to the defined
`,-conten't ofconstituents, using suitableinert materials or a
`extract of? the vegetable or animal matter used‘ for the
`4 _preparation.«
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`- Where’ applicable, the monograph on a dry extract
`presjcri_b__es- a_.1itnit test for the solvent used for extraction.
`TESTS
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`Eyepreparations are sterile, liquid, semi-solid orsoiid
`preparations~ intended for administration upon the eyeball
`andfor to 5th_"e’conjunctiva or to be inserted in the conjunc-
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`tival sac.
`'
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`Where applicable, containers for eye preparations
`comply ‘with the_require_ments ofMotm'als Usedfor the
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`1l{Iar:ufo‘otu‘re of Container: (3.! and subsections) and
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`Contoimars (3.2 and subsections).
`Several categories of eye preparations may be
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`distinguished:
`—-- eye drops,
`—- eye lotions,
`— semi-solid eye preparations, ,
`~_~— ophthalmic inserts.
`PRODUCTION
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`Loss on drying (2.232). Where applicable, the dry
`egttract complies withjthe limitsprescribed in the mono‘-
`graph. In a flat«-bottomed dish about 50 turn in diameter
`and about 30 mm in h'eight,_weigh rapidly 0.50 g ofthc
`extract to be exarniried, finely po'_wdered..D.ry in an oven at
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`1‘00?(-2 to 105"-.C-I for 3 h. Allow to cooi in a de'sic'c_ator_ over
`-:—d£phot_okon¢s.pegzroxide.R and weigh. Calculate the result. as
`'3 PRESS jP3ICCfltEg€t_
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`"STORAGE ‘-
`. Stgre in
`a_i1ftig_ht_contairier, protected from light.
`‘ LABELLENG ‘
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`'During the development of an eye preparation, the formu-
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`lation for which contains an antimicrobial preservative, the
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`effectiveness cfthe chosen preservative shall he demon-
`strated to the satisfaction of r.he;co'_rnpetent authority.,A
`suitable method of test together with criteria for judging‘
`the preservative properties of the formulation are provided
`
`in the text on Eflicacy ofA11n'microbiolPz-eseruation (5.13).
`Eye preparations are prepared using materials and
`‘_ use ..1.=‘a1>'«'=1.s:;'a‘:‘«‘=s=.’i f
`methods designed to ensure sterility and to avoid the
`'—- the nameland aniouht of any inert material used,
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`introduction of contaminants and the growth of tn'icro-
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`tho‘.-_\_re‘g_e'ta‘5le or a'ri_irnal matter used,
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`organisms; recommendations onthis‘ aspect are provided
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`-—— where ’app1ic'able, that fresh vegetable or animal .1'na_1__'te1‘
`in the text on Methods offireporanon of Sterile Products
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`was \_1s'e'd,
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`(5.I.1).
`_ -1- the name and the ethanol content in per cent VIV of
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`In the manufacture of eye preparations containing
`“tee s9j1i¥i:jxir_u'é_j;eiE1_ fdijthe preparation,
`‘dispersed particles measures are taken to ensure a suitable
`~‘-.-tlzie‘foohtent of‘ao't_ive- principle andlor the ratio of
`and controiledrparticle size_ with regard to the intended
`" ' "start_in'g'material to final ‘dry extract.
`use.
`Ph Eur
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`TESTS
`Sterility (2. 6. 1). Eye preparations. comply with the test
`f_ot,sterili_1y. Applicators ‘supplied separately also comply
`with the test for‘sterility._Removc the applicator with
`aseptic precautions from its. package and transfer it to a
`tube of culture mediuni. so, that it is completely immersed.
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`Incubate and interpret the results as described in the test
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`for sterility.
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`STORAGE
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`Unless otherwise prescribed, store in a sterile, airtight,
`tamper-proof container.
`LABELLING
`The label states the name of any added antjrnicrobial
`preservative.
`'
`
`Eye-drops
`DEFINITION
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`jj;*-fgigtraotsjfoi thefilfgjritish Pharmacopoeia
`
`i
`...
`.
`.
`I
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`.1.-,w :-.'_.'
`.. tr‘
`¢'r_c;r_ore the Subject of an mdwtduol mona-
`. Iiaioflowwa
`c_zpig:?~i't_’r.F:“'e'7’_B_ _ii1;I;"'Lifl?Ic_§1}:acopoeia. Those d:'sn'ngm'shed by the
`
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`~
`.
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`.siv‘2_'i13ol_‘il'
`the or _beio:io are monographs of the European
`'PIizzr'75eiz¢o1:‘ae'za;
`Aloes Dry Extract, Standardised ‘fit
`Belladonna Dry Extract
`Cascara Dry Extract
`Frangula Bark Dry Extract, Standardised ti‘?
`Hyoscyamus Dry Extract
`Ipecactianha Liquid Extract
`Liquorice Liquid Extract
`Quillaialiquid Extract
`Senna Leaf Dry Extract, Standardised it
`Senna Liquid Extract
`Squill Liquid Extract
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`

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`3-I‘!
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`1429
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`ailon into the eye. When the stability of the final prepara-
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`.£-m “quires it, the medicinal substances may be supplied
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`in’; dry, sterile form to be dissolved or suspended in an
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`‘pp;-‘opgiare sterile liquid immediately before use.
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`,. gypdmps may Contain excipients, for example, to
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`iust the tonicity or the viscosity of the preparation, to
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`fidiust or stabilise the pH, to increase the solubility of the
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`. 5‘-C15,,-e mgredienr, or to stabilise the preparation. These
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`'. balances do not adversely afifect the intended medicinal
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`aidtion or. at the concentrations used, cause undue local
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`" ' iution.
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`‘irfiqucous preparations supplied in multidose containers .
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`contain a suitable antimicrobial preservative in appropriate
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`.‘ :¢o"ncent.ra'tion except when the preparation itself has
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`‘adequate antimicrobial properties. The antimicrobial
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`..‘p7i-escrvative chosen are compatible with the other ingre di-
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`1‘; oi’ the.prep_aration and remain elfcctive throughout
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`«me period of time during which eye—drops are i.n use.
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`' ~ It eye-drops arefprescribed without antimicrobial preser-
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`,'- yritives they are supplied wherever possible in single-dose
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`. containers. Eye-drops intended for use in surgical proced-
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`_ supplied in single-dose containers.
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`. Eye-_drops that are solunons, examined under suitable
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`‘-."cohdi'ti_tSns of visibility, are practically clear and practically
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`free from particles.
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`—Eye—drops 't.h|r‘arv_b suspensions may show a sediment
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`that is‘ readily dispersed on shaldng to give a suspension
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`.. which r‘ern'ains sufliciently stable to enable the correct dose’
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`‘be delivered.
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`_Mu1tidosc preparations are supplied in containers that
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`.'g.ll_ow successive drops of the preparation to be adminis-
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`_tered. The containers contain at most 10 ml of the prepar—‘
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`upon. unless othenvisejustizfied andautboris‘ed.
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`'~BS_"I‘S__ ‘.
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`,_:_trtic1e siz'e-‘Bye-drops in the form of a suspension
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`.c?ii'hply with “tile following rest: introduce a suitable ‘quant-
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`_ ‘iii; of the suspension into a counting cell or with a micro-
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`f {pipc'ttc;onto a slide,"as appropriate, and scan under a
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`' ' Efiicroscope arrarea corresponding to 10 pg of the solid _
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`’pl1ase. For practical reasons, it is recommended that the
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`_“ -wliblc sample is firstl scanned at low magnification (e.g.
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`.
`"
`V
`.-
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`'~X50) and particles greater than 25 um are identified.
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`’-These larger particles can then be measured at a large
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`_magnification tefgt X200 to X500). flat more than twenty
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`‘haves maxirnum dimension ,
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`",paI:l:1.cles'' V
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`of these articles have a maximum
`dznot more than‘ -
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`dimension greater than 50 um. None 0 the particles has a
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`: an 90 inn.
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`The labei states that for multidose containers, the period
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`' after opening the container after which the contents must
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`not be used. This period does not exceed 4 weeks, unless
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`Otherwise iustificd and authorised.
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`I Eye Lotions.
`DEFINI'I‘l0N
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`Eye lotions are sterile aqueous solutions intended for use
`In washing or bathing the eye or for impregnating eye
`- dressings.
`Elle lotions may contain excipicnts, for example to
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`sciy affect the intended action or, at the concentrations
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`used, cause undue local irritation.
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`Eye lotions supplied in multidose containers contain a
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`suitable antimicrobial preservative in appropriate concen-
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`tration except when the preparation itself has adequate
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`antimicrobial properties. The antimicrobial preservative
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`chosen is compatible with the other ingredients of the
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`preparation and remains effective throughout the period of
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`time during which the eye lotions are in use.
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`If eye lotions are prescribed without an antimicrobial
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`preservative, they are supplied in single-dose containers.
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`Eye lotions intended for use in surgical procedures or in
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`first«aid"trea,tli:ient do” not contain “an antimicrobial prescr-
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`vative and aresupplied in containers intended for use on
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`one occasion only.
`i
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`Eve lorioiis 'eiEan1ined‘undér suitable. conditions of
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`visibility, are iiracficaliir clear and p_'r_a_c_tic_ally free fiom
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`particles.
`4
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`The containers for multidose preparations do not
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`contain more than 200 ml of ‘eye lotion, unless otherwise
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`justified and authorised.
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`LABELLl1\lG
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`The label states:
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`— for single-dose preparations, that the contents are to be
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`used on one occasion only,
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`—'forin’ultidose preparations, the periodafter opening the
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`container after 'wh.'tch'the c<SntEi1ts~r'n1.tsft not be used.
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`This period does not éiicee'd 4 weeks, unless otherwise
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`iustified ah'd'autl:1‘orise‘d.
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`Semi-So1id;Eye Preparations
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`.'i3a1=nxIrr1,o1~_I,
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`-I "Semi-solid;eye.ps;;;.-_rasonsrarigsterile ointtnents, creams
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`. or gels-intended fo_r‘appl_ication"to_ the ‘conjunctiva. 'I'he*y
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`. ‘contain oneor more a¢_:tiv‘e_,_,ir'igrcdients dissolved or
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`disp_ersed_in a"?s’i1itab'le basis,"I'liey-have a homogeneous
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`appearance.
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`Sernigsolid eye preparations comply with the require»-
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`ments of tlueptonograph on;«1"aj2ica'I senii:-solidprépararions
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`(132). The basis‘-is’nori¥-i.r1_5il:z_1nt'to the conjunctiva.
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`Semi-solid eye’ preparatiiins are packed in small‘, steril-
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`ised collapsible tubes fittedizvr provided with a cannula and
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`having a content of not more than 5 g of the preparation.
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`The tubes must be we1l~c':1osed toprevent microbial cont-
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`amination."Séini-=solid eve ‘preparanons may also be
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`packed in suitably-designed‘ single-zdose containers.
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`‘
`TESTS
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`Particle size Semi-solid eye‘p'r‘cparations containing
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`dispersed solid particles comply with the following test:
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`spread g'c'ntly'a quantiry_oftl_1e preparation corresponding
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`to at least 10 gig ofsolid active ingredient as a thin layer.
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`Scan under a microscope the whole area of the -salnple.
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`For practicalreasons, it is recommended that the whole
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`‘sample is first-scanned at a-small magnification (c.g. X50)
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`and particles greater than 25 pun‘ are identified. These
`larger particles can then be measured at a larger magnifi-
`cation (e.g. X200 to X500). For each 10 pg of solid active
`ingredient, not more than twenty particles have a maxi-
`mum dimension greater than 25 pm, and not more than
`tW0.0fT.'£1BS_t.‘. particles have a maximum dimension ‘greater
`than 50 um. None of the particles has a maximum ditnen-'_
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`02534’/2A1
`039l3'69A2
`0480690/X1
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`[19]
`United States Patent
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`[45] Date of Patent:Aviv et al. Mar. 5, 1996
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`[11] Patent Number:
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`5,496,811
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`JmmmmlmumIlillmgggglggllltulllnlmlmllulu
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`.
`]/I983 European Pat. Clfi’.
`
`
`10/1990 European Pat. 011'. .
`4/1992 European Pat. Off. .
`
`OTHER PUBLICATIONS
`
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`Hardbergcr, R., "Effects ofDrug Vehicles on Ocular Contact
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`Time”, 93 :42-45 (1975).
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`Primary Examiner—Zoh1'eh Fay
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`Attorney, Agent, or F£zm—Pennie & Edmonds
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`ABSTRACT
`[57]
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`An ocular drug delivery vehicle of an oil-in-water submi-
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`cron emulsion comprising about 0.5 to 50% of a first
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`component of an oil, about 0.1 to 10% of a second compo-
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`nent of an emulsifier. about 0.05 to 5% of a non-ionic
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`surfactant and an aqueous component, with the mean droplet
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`size being in the submicron range, i.e., below about 0.5 um
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`and preferably between about 0.1 and 0.3 pm Also, topical
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`pharmaceutical compositions containing a drug such as an
`anti-glaucoma drug, beta adrenergic blocker or other auto-
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`nomic system drug, a local anesthetic, a steroid, a non-
`steroidal anti-inflammatory drug, an antibiotic drug, an
`antifungal drug, an antiviral drug or combinations thereof
`and the vehicle described above. Methods of administering
`such vehicles or compositions to the eye of a patient while
`reducing irritation thereof and providing increased bioavail-
`ability of the drug.
`
`[75]
`
`[54] SUBMJCRON EMULSIONS AS OCULAR
`
`
`
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`DRUG DELIVERY VEHICLES
`
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`Inventors: Haim Aviv, Rehovot; Doron
`
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`Friedman, Carmei Yosscf; Arm‘:-
`Bar-llan, Neve Monsson; Micha
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`Vered, Rchovot, all of Israel
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`[73] Assigneo: Pharmos Corp., New York, N.Y.
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`[21] App]. No.: 854
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`[22] Filed:
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`Jan. 5, 1993
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`Foreign Application Priority Data
`[30]
`
`Aug. 28,1992
`[IL]
`Israel ........................................ 102984
`
`Israel ........................................ 103907
`Nov.27, 1992
`{IL}
`
`
`A61K 31/635; A6IK 31/66;
`[51}
`Int. Cl.“
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`
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`A61K 31/22; A61K 31/225
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`514f/8; 514/75; 514/76;
`
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`514/546; 514/547; 514/560; 514/912
`514/76, 75, 73,
`[58] Field of Search
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`
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`514/912, 546, 547, 560
`
`[52] US. Cl.
`
`[56]
`
`_
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9/1981 Penley ..................................... 198/470
`4,289,080
`4/I990 Glonek et a1.
`............................ 514/76
`4,914,083
`FOREIGN PATENT DOCUMENTS
`
`0028110113
`
`5/1981
`
`European Pat. Off. .
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`
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`37 Claims, 3 Drawing Sheets
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`U.S. Patent
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`Mar. 5, 1996
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`Sheet 1 of 3
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`5,496,811
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`intnaoculanpressure(mmHg}
`
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`intnaoculonpressure(mmHg)
`
`P0O1
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`O*--0 baseline IUP
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`o--——o
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`treat ed IOP
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`I00
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`.5 5
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`2}?
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`O
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`5
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`25
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`30
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`hours after treatment
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`FlG.1
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`35
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`IQU1
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`o———-—o baseline IOP
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`0—————o
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`contnalutenol
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`IOP
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`—.h on
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`IN)C)
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`0
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`5
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`10
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`15
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`25
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`30
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`35
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`hours after treatment
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`I-18.2
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`U.S. Patent
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`Mar. 5, 1996
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`Sheet 2 of 3
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`5,496,811
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`diameter-mm
`Pupil
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`0
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`1 0
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`20
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`T i me (hours)
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`30
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`—Q—— right eye -pi ioccmpine
`._o_ right eye -emulsion
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`FIG. 8
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`Pupildiometen-mm
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`0
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`10
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`20
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`Time (hours)
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`-—.— nigh: eye
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`-0- left eye
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`FIG. 4
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`U.S. Patent
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`Mar. 5, 1996
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`Sheet 3 of3
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`5,496,811
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`Directed night eye
`non - treated left
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`eye
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`16
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`2.7/////4//Ao.|.3
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`Time (hours)
`
`F106
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`""."‘_‘.""“—’/.
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`5,496,811
`
`SUBMICRON EMULSIONS AS OCULAR
`DRUG DELIVERY VEHICLES
`
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`1
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`2
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`the residence time of drugs in the eye and hence some
`
`enhancement of the ocular bio-availability, such carriers also
`produce various deleterious side efiects. See Harmia et al.,
`FIELD OF THE INVENTION
`supra, Saettone et al. (1988) J. Pharm. 43:67-70 and Meis-
`
`
`
`ner et al. (1989) Int. J. Pharm. 55:105-113.
`
`
`
`
`
`
`
`
`
`
`
`
`The present invention relates to the field of drug delivery
`Emulsions have also been suggested as vehicles for
`and, particularly, to the administration of various pharma-
`delivery of drugs to the eye in references such as EP
`ceutical agents to a patient through the eye by application of
`
`
`
`
`
`391,369, Ellis et al. (1987) J. Ocular Pharmcol. (U.S.)
`
`
`the innovative compositions of these agents in a non-
`3:l2l—l2S,
`and
`Shell
`(1934)
`Surv. Ophthalmol.
`irritatiug submicron emulsion.
`
`29:177-178. Nevertheless, the practical inability to realize
`
`the potential of emulsion systems for ocular drug delivery
`
`stems predominantly from two problems. First, ocular drug
`formulations must be comfortable to the patient as well as
`
`safe, due to the sensitivity of the delicate eye tissues
`
`involved. Second, emulsions are generally metastable dis-
`
`
`
`persions of immiscible fluids and these instability problems
`must be overcome.
`
`
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`10
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`35
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`
`BACKGROUND OF THE PRESENT
`INVENTION
`
`
`
`The primary problem associated with topical applications
`
`
`
`of drugs to the eye is that the human eye is a very sensitive
`organ and any substance which is not compatible with it
`causes irritation and pain. This evokes blinking and reflex-
`
`
`
`An emulsion is a dispersion of oil in water (“o/w”), and
`tearing, which is a physiological reaction intended for
`
`
`can be defined as either a macroemulsion or a mieroemul-
`
`removal of the irritating substance from the ocular surface.
`2D
`
`sion. A macroemulsion is a cloudy turbid composition
`Irritation is a major cause of poor patient compliance with
`
`
`having an oil-droplet size of 0.5 to 100 pm and is generally
`
`
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`
`
`many ophthalmic drugs. This phenomenon is aggravated by
`thermodynamically unstable. In comparison, a mieroemul-
`
`the need to include relatively high concentrations of a drug
`sion is a translucent to transparent composition having a
`in such ophthalmic compositions in order to obtain a thera-
`
`droplet size of 0.005 to 0.5 urn, is thermodynamically stable
`
`
`peutic elfect, since bioavailability of topically applied oph-
`and is generally self emulsifying. See, e.g., Friberg et al.
`thalmic drugs is generally very poor. Thus, there is no doubt
`(1987) Microemulsions Structure and Dynamics, CRC Press
`
`
`
`that a reduction in the irritating eifect of a dmg will enable
`Inc., Boca Raton. Fla, pp. 154. Also, the proportion of
`
`
`
`
`surfactants to oil required to generate mieroemulsions is
`increased ocular drug bioavailability, increased patient com-
`
`
`
`generally much higher than in rnacroemulsions.
`
`pliance with the drug, and enhanced therapeutic efiicacy of
`
`the drug.
`-
`Emulsions developed specifically forophthalmic use have
`30
`attempted to solve the problem of inherent
`instability
`Currently, aqueous solutions are by far the most common
`
`
`through the use of mieroemulsions or the addition of stabi-
`vehicles for ophthalmic drugs. Such vehicles have a serious
`
`lizing polymers to classical emulsions. In several instances,
`drawback, however, in that the ocular bioavailability of
`
`specific drugs have been formulated successfully in micro-
`drugs administered thereby is generally very poor due to
`
`
`
`
`
`
`
`
`
`emulsions. Examples of this approach include ophthalmic
`rapid drainage and tear turnover. See Fitzgerald et al. (1987)
`mieroemulsions of tepoxalin, as disclosed in EP 480,690, or
`J. Pharm. Pharmacol. 39:487-490. A typical dose of oph-
`flurbiprofen, as disclosed in EP 253,472.
`thalmic solution is in the range of about 50-100 pl, which far
`
`An alternative approach to solve the problem of emulsion
`exceeds the normal lachrymal volume of about 7-10 pl.
`instability utilizes lightly crosslinlted polymers, as exempli-
`
`Thus,
`the portion of the dose that is not eliminated by
`
`
`fied by the autoclavable emulsions for ophthalmic use which
`
`40
`spillage from the pulberal fissure is quickly drained. Fur-
`are disclosed in EP 028,110.
`
`
`
`
`
`
`
`
`
`
`thermore,
`lachryrnation and physiological
`tear turnover,
`
`which in humans is about 16% per minute under normal
`conditions, increases after the introduction of the solution,
`resulting in rapid dilution of the remaining amount of drug
`
`
`
`that has. not been spilled or drained. As a consequence, the
`
`contact time with the absorbing surfaces of the eye (i.e., the
`cornea and sclera) of drugs which are applied to the eye via
`
`
`
`
`
`liquid aqueous compositions is less than about two minutes.
`Another drawback of aqueous vehicles is that many drugs
`which may potentially be used in eye therapy are hydro-
`phobic and their delivery into the eye by such aqueous
`
`
`
`
`
`
`
`
`vehicles is not possible. While such hydrophobic drugs may
`
`potentially be administered to the eye in conjunction with
`various organic solvents, the use of such solvents usually
`causes irritation and inflammatory reactions. See Harmia et
`al. (1987) Pharm. Acta Helv. 62:322-332.
`
`
`
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`55
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`
`The present invention solves the problem of emulsion
`instability without resorting to either of the prior art sug-
`
`
`
`gestions by instead converting classical emulsions to sub-
`
`
`
`
`micron emulsions with the input of energy by shear forces
`and homogenization to provide submicron emulsions pos-
`sessing substantially reduced eye irritation properties. Also,
`the irritation of the eye is further reduced through the use of
`non-irritating non-ionic surfactants in such emulsions. Thus,
`
`when drugs are included with these submicron emulsions,
`the present
`invention provides ophthalmic compositions
`which are improved over those which are currently available
`in the art. In accordance with the present invention, eiiective
`means for reducing irritation of the eye, particularly such
`irritation which is drug-induced, is provided for the first time
`and thereby along felt need has been fulfilled.
`SUMMARY OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`
`
`
`
`
`
`Attempts have been made to develop various delivery
`vehicles in which the drug residence time in the eye is
`increased. The most direct approach for achieving this goal
`is by an increase in the viscosity ofthe vehicle. Thus, various
`viscous vehicles, such as liydrogels or ointments, have been
`attempted, some of which also enable delivery of hydro-
`phobic drugs into the eye. Additionally, many attempts to
`use various non-conventional carriers, such as liposomcs,
`micellar solutions and nanoparticles, as vehicles of oph-
`thalmic drugs have also been made. While the use of such
`
`
`
`
`
`45
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`50
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`
`
`In addition, the use of emulsions in ophthalmic prepara-
`
`tions has been limited to a large extent by the inclusion of
`surfactants in the emulsions which surfactants are highly
`irritating to the eye. For example, the use of the emulsion
`preparations of EP 391,369 are limited considerably by the
`irritating cifect of the ionic surfactants which are used in
`
`those emulsions. Thus, to date no commercially successful
`
`
`
`
`
`
`ophthalmic compositions in the form of oil-in-water emul-
`sions are available.
`
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`

`

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`5,496,811
`
`
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`4
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`3
`
`versus baseline in both treated and contralateral eyes with a
`
`about 0.5 to 50% of a first component of an oil, about 0.1 to
`comparison to the administration of the same emulsion
`
`10% of a second component of an emulsifier, about 0.05 to
`
`
`
`
`
`
`without pflocarpine; and
`
`5% of a non-ionic surfactant and an aqueous component,
`
`
`FIG. 6 shows the change in IOP versus baseline level in
`with the mean droplet size being in the submicron range, i.e.,
`
`human subjects following administration of a 2% pilo-
`below about 0.5 pm and preferably between about 0.1 and
`
`carpine containing emulsion versus for both treated and
`
`0.3 pm.
`
`
`
`contralateral eyes with a comparison to the administration of
`
`
`
`
`
`
`The first component may be a medium chain triglyceride
`
`the same emulsion without pilocarpine.
`
`
`
`oil, a vegetable oil, a mineral oil or mixtures thereof, and is
`
`
`
`
`
`DETAILED DESCRIPTION OF THE
`usually present in an amount of about 1 to 20%. For viscous
`
`
`
`INVENTION
`
`compositions or creams, the oil may be present in an amount
`
`of about 30 to 50%.
`
`
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`10
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`1'5
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`20
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`'
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`30
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