United States Patent [19]
`Cavanak
`
`[54] GALENICAL COMPOSITIONS
`
`[75] Inventor: Thomas Cavanak, Oberwil,
`Switzerland
`
`[73] Assignee: Sandoz Ltd., Basel, Switzerland
`
`[21] Appl. No.: 347,276
`
`[22] Filed:
`
`Feb. 9, 1982
`
`[63]
`
`Related US. Application Data
`Continuation-in-part of Ser. No. 208,181, Nov. 19,
`1980, abandoned, which is a continuation-in-part of
`Ser. No. 82,487, Oct. 9, 1979, abandoned, which is'a
`continuation of Ser. No. 16,950, Mar. 2, 1979, aban
`doned.
`
`Foreign Application Priority Data
`[30]
`Mar. 7, 1978 [CH] Switzerland ....................... .. 2461/78
`Mar. 14, 1978 [CH] Switzerland ....................... .. 8634/78
`
`[51] Int. Cl.3 .................... .. A61K 37/00; A61K 47/00
`[52] US. Cl. ................................ .. 424/ 177; 424/365
`[58] Field of Search .............................. .. 424/177, 365
`
`[1 1]
`[45]
`
`4,388,307
`Jun. 14, 1983
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,288,824 11/1966 Mahier et a1. ..................... .. 424/365
`3,881,012 4/1975 Mirna et al.
`424/365
`4,073,920 2/ 1978 Dowrick ......... ..
`424/365 .
`4,108,985 8/1978 Riiegger et al. .................. .. 424/177
`
`FOREIGN PATENT DOCUMENTS
`
`2253531 12/1974 France .............................. .. 424/ 177
`2330387 11/1976 France .... ..
`424/177
`2390420 5/1978 France .............................. .. 424/ 177
`Primary Examiner—Delbert R. Phillips
`Attorney, Agent, or Firm-Gerald D. Sharkin; Robert S.'
`Honor; Walter F. Jewell
`[57]
`ABSTRACT
`The present invention provides a pharmaceutical com
`position comprising a pharmacologically active mono
`cyclic peptide and a carrier comprising at least one of
`the following components:
`(a) a non-ionic ester of a triglyceride and a polyalkylene
`polyol,
`(b) a saturated fatty acid triglyceride, and
`(c) a mono- or di-glyceride
`,
`having improved physical and absorption properties.
`
`15 Claims, No Drawings
`
`NOVARTIS EXHIBIT 2108
`Par v Novartis, IPR 2016-00084
`Page 1 of 6
`
`

`
`1
`
`GALENICAL COMPOSITIONS
`
`4,388,307
`tional pharmaceutical vehicles, in particular cyclospo
`rins, including those having a basic ring structure as
`follows:
`
`CH3 CH3
`\
`CH3 CH3
`CH
`\
`l
`CH3 CH
`CH2
`CH3—N—CH—CO—N—-CH—CO
`I L
`L
`CO
`I
`CH—CH2—CH L
`.
`|
`CH3—N '
`D
`
`L
`
`-
`
`CH3
`
`CH3
`
`A
`
`$113
`N-CH;
`
`co
`
`N—CH2
`
`L
`
`o
`H L
`
`H
`|
`
`L
`
`OC-(fH-N'-CO'-(fH—N-CO-CH-liI-C-CH-N-CO-(EH
`CH3 H
`CH3
`CH2 CH3 CH
`CH;
`CH
`CH3 CH3
`CH
`/ \ -
`CH3 CH3
`
`CH3 CH3
`
`30
`
`40
`
`45
`
`This is a continuation-in-part of our co-pending appli
`cation Ser. ‘No. 208,181, ?led Nov. 19th, 1980, now
`abandoned which in turn in a continuation-in-part of
`our application Ser. No. 82,487, ?led Oct. 9th, 1979,
`now abandoned, which in turn was a continuation of 25
`our application Ser. No. 16,950, ?led Mar. 2nd, 1979,
`now abandoned.
`This invention relates to galenical compositions, par
`ticularly compositions containing a pharmacologically
`active mono-cyclic peptide.
`Because of the hydrophobic and/or lipophilic char
`acter of such peptides, pharmaceutical formulations
`thereof with conventional solid or liquid pharmaceuti
`cal excipients tend to have disadvantages, For example
`the peptide may not be satisfactorily absorbed, the com
`35
`position may not be well tolerated, the composition may
`not be sufficiently stable on storage, e.g. against crystal
`lizing-out of the peptide, and/or the concentration of
`the peptide capable of being solubilized without crystal
`lizing-out may be low, e.g. of the order of 3% or lower.
`Problems of this nature arise not only with liquid
`formulations, but such solid forms such as solid “solu
`tions”, e.g. in the form of oral pellets, produced for
`example by melting a solid carrier, mixing in the active
`ingredients and allowing the mixture to solidify. I
`While there are many known proposals to alleviate or
`overcome problems of this type, it has been found after
`exhaustive trials that many of these proposals are inade
`quate in the area of the monocyclic peptides, in particu
`lar cyclosporins, with which the invention is concerned.
`It has, however, surprisingly been found that certain
`classes of glycerides used as carrier components do
`assist in alleviating these difficulties; in particular they,
`for example, may enable achievement of higher blood
`levels of active agent or avoid other problems such as
`instability.
`The present invention accordingly provides a phar
`maceutical composition comprising a pharmacologi
`cally active mono-cyclic peptide and carrier comprising
`at least one of the following components:
`.
`(a) a trans esteri?cation product of a natural or hy
`drogenated vegetable oil triglyceride and a polyal
`kylene polyol,
`(b) a saturated fatty acid triglyceride, and
`(c) a mono- or di-glyceride.
`The compositions of the invention are particularly
`suitable for hydrophobic and/or lipophilic peptides
`which are insoluble or dif?cultly soluble in conven
`
`55
`
`65
`
`wherein A is a bivalent moiety containing two amino
`acids linked together.
`A may be for example:
`
`(cyclosporin A)
`
`CH3 H
`\ /
`C
`II
`C
`' /
`H
`
`CH2
`
`HO (R) CH (R) CH3
`\ /
`l
`CH3 CH CH3 CH2
`
`—N—CH—CO—liI-CH—CO—
`
`L
`H ( )
`
`L
`( )
`
`“3C
`
`(‘m2
`HZC
`
`9“
`
`HO (R) CH (R)
`
`CH3
`
`(dihydro
`c clos rinC
`y
`p0
`)
`
`(cyclosporin D)
`.
`
`CH3 H
`\ /
`C
`II
`C
`
`H
`
`CH2
`
`H0 (R) CH (R) CH3 CH3
`\ / \
`\ /
`CH3 CH CH3
`(III-l
`—N—CH—CO—N——CH-CO—
`(L)
`‘I;
`(L)
`
`NOVARTIS EXHIBIT 2108
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`Page 2 of 6
`
`

`
`3
`-continued
`
`CH3
`\
`CH;
`HZC
`
`CH2
`HO (R) CH (R) CH3 CH3
`\ \
`\ /
`(‘3H3 CH
`CH3
`CH
`—N-—CH—CO—I’l~I-—CH-CO—
`
`H
`
`L
`( )
`
`(L)
`
`(dihydro
`cyclosporin D), or
`
`4,388,307
`4
`number: 145-175 and a hydrophilic-lipophilic balance
`(H.L.B.)=4).
`Component (b) may be obtained in conventional man
`ner by esterifying a triglyceride with saturated fatty
`acids having a carbon chain length of 8 to 12 carbons.
`Generally these glycerides will have an iodine number
`of less than 2. Examples of the triglycerides with which
`this invention is concerned are the MIGLYOLS @
`(Dynamit Nobel Witten/Rukr Germany), especially
`Miglyol 812, or Myritol 318 (Henkel Diisseldorf, Ger
`many). The physical and chemical composition of Mi
`glyols are shown in Table I.
`TABLE I
`MIGLYOL 810 MIGLYOL 812 MIGLYOL 818 MIGLYOL 840
`
`10
`
`PHYSICAL CHARACTERISTICS
`Acid value
`0.1 max.
`0.1 max
`0.1 max.
`0.2 max.
`saponi?cation value
`320-340
`340-360
`325-345
`315-320
`1 max.
`1 max.
`1 max.
`10 max.
`Iodine value
`Unsaponi?able matter (%)
`0.3 max.
`0.3 max.
`0.3 max.
`0.2 max.
`Iodine colour value
`2.0 max.
`2.0 max.
`2.0 max.
`3.1 max.
`Cloud point
`—10° C. max.
`0° C. max.
`10° C. max.
`10“ C. max.
`Moisture (%)
`0.15 max.
`0.15 max.
`0.15 max.
`0.15 max.
`0.92-0.94
`0.94-0.96
`0.94-0.96
`0.93-0.95
`Density at 20° C.
`l.440-1.442
`l.4490-1.4510
`l.4480—1.4500
`l.4490—l.45l0
`Refraction at 20° C.
`9-12
`27-30
`28-32
`30-33
`Viscosity at 20° C. (cps.)
`DISTRIBUTION OF THE FATTY ACIDS IN THE GLYCERIDE
`
`Fatty Acids
`Hexanoic acid (C6)
`Octanoic acid (Cg)
`Decanoic acid (C10)
`Laurie acid (C12)
`Linoleic acid (C13)
`
`2% max.
`65-75%
`25-35%
`2% max.
`
`3% max.
`50-65%
`30-45%
`5% max.
`
`3% max.
`45-60%
`25-40%
`2—5%
`
`3% max.
`65-80%
`15-30%
`3% max.
`
`—
`
`-—
`
`3-6%
`
`-—
`
`(iso-cyclosporin D)
`
`35
`
`CH3 H
`\ /
`C
`ll
`C
`
`H
`
`CH2
`
`0 (R) CH (R) CH3 CH3
`\ / \
`\ /
`(III-1
`CH3
`(‘3H
`HIiI—-CH—CO—1'~1——-CH—CO—
`
`H
`
`L
`( )
`
`L
`CH3 ( )
`
`45
`
`Cyclosporin A, dihydrocyclosporin C and isocyclospo
`rin D are the preferred peptides. Cyclosporins e.g. as
`identi?ed above are known compounds having known
`pharmacological activity, e.g. as described in U.S. Pat.
`Nos. 4,117,118 and 4,108,985 and in Belgian Pat. No.
`866,810.
`Component (a) may be prepared in conventional
`manner, e.g. as described in U.S. Pat. No. 3,288,824.
`The ester may be formed by transesteri?cation of a
`triglyceride particularly a triglyceride from a vegetable
`oil, e.g. from kernel oil, almond oil, ground nut oil, olive
`oil and/or palm oil, with one molar part of a polyethyl
`ene glycol MW 200 to 800 and obtainable according to
`the process described in the U.S. Pat. No. 3,288,824
`mentioned before, the contents of which are incorpo
`rated by reference. These esters may be obtained from
`Etablissement Gattefosse, Boulogne sur Seine, France,
`under the trade name LABRAFIL (see Fiedler, Lexi
`kon der Hilfstoffe p. 320, 1971). The preferred ester is
`Labra?l M 1944 CS (a polyoxyethylated kernel oil)
`mixture having a density D2°=0.940—0.965, an acid
`number <2, an iodine number=60—90, a saponi?cation
`
`55
`
`60
`
`65
`
`Component (0) is preferably one of the mono- or
`di-glycen'des approved for pharmaceutical use, e.g. a
`mono- or di-(C16-C20) fatty acid glyceride, e.g. of stea
`ric acid or especially of oleic acid. Preferably compo
`nent (c) is glycerol mono-oleate (Monooleinum-Phar
`macopoea Helvetica Sixth Edition).
`Naturally when the components (a) and/or (0) pres
`ent are solid, these should be chosen such that they can
`be melted at temperature at which the peptide is stable.
`Such components include, for example, glycerol mono
`stearate or glycerol di-stearate, and Labra?l 2130.
`The preferred total concentration of component (a)
`and/or component (b) and/or component (c) present in
`the pharmaceutical compositions according to the in
`vention, as well as the weight ratio of individual compo
`nents when two or more of these are present, will natu
`rally depend, inter alia, on‘ the particular component(s)
`used, and in particular on the solvent/solubilizing effect
`thereof, the particular mono-cyclic peptide used, the
`concentration of mono-cyclic peptide desired in the
`?nal composition and the solvent/solubilizing effect of
`any further pharmaceutical excipients present. In gen
`eral the preferred weight ratio of component (a), (b)
`and/or (0) to peptide is 10 parts in total of the compo
`nent (or components) to 0.2 to 10 parts of peptide, or
`more preferably 1 to 10 parts by weight of peptide, and
`conveniently from 1 to 7 parts by weight of peptide.
`The pharmaceutical compositions of the invention
`may be made by mixing a pharmacologically active
`mono-cyclic peptide with the liquid carrier comprising
`component (a) and/or (b) and/or (c) as de?ned above.
`If the component (a) or (c) is solid, temperatures up to
`about 70° C. may be used, to produce a liquid melt in
`which the active agent may be dissolved in. The com
`position may be cooled and then, for example, ground.
`
`NOVARTIS EXHIBIT 2108
`Par v Novartis, IPR 2016-00084
`Page 3 of 6
`
`

`
`20
`
`25
`
`4,388,307
`5
`6
`The pharmaceutical compositions may be formulated
`rier comprising all three ingredients, no precipitation of
`in conventional manner, if desired with further pharma
`the cyclosporin is observed on storage over longer
`periods of time, both at lower and elevated tempera
`ceutical excipients, into forms suitable for oral or paren
`teral administration. Preferably they are in liquid form.
`tures, e.g. at temperatures of from 5° to 50° C., even
`Examples of preferred compositions are:
`when higher concentrations of cyclosporin, e.g. as af
`(a) Solutions for drinking, e.g. Example 1 hereinafter,
`foresaid, are present. The compositions of the invention
`(b) Emulsions for drinking,
`thus have the advantage of a greatly improved shelf-life
`with reduced temperature criticality. Unlike composi
`(c) Injection solutions, e.g. Examples 2 and 4 herein
`tions in which one of the ingredients (i) and (iii) is omit
`after,
`_
`(d) Solutions contained in capsules, e.g. Example 6
`ted, they can be transported and kept in reserve at both
`hereinafter,
`lower and elevated temperatures, for periods in excess
`(e) Pellets for oral administration.
`of several months for later use as, and when, required.
`Compositions comprising a three component system
`The modes of administration are preferably intramus
`(a)+(i)+(iii) also have the advantage of providing a
`cular and subcutaneous administration or more prefera
`bly oral administration. In particular when component
`self-emulsifying system in the presence of water, with
`(b) is present, the pharmaceutical composition is prefer
`out immediate precipitation of the active ingredient.
`ably used for parenteral administration.
`This is of importance in respect to the bio-availability of
`The pharmaceutical compositions according to the
`the active agent, since precipitation in e.g. the aqueous
`invention may be formulated with or without further
`medium of the stomach or on intra-muscular injection
`exipients.
`leads to severely impaired resorption. ‘The occurrence
`of problems in relation to cyclosporin bio-availability
`In particular solubilizing agents and solvents may be
`employing hitherto known formulations has been
`present in a concentration of up to 60% of the total
`composition, if desired, in order to attain a satisfactory
`recognised and discussed e.g. in Calne et al., “IRCS _
`Medical Science; Drug Metabolism and Toxicology;
`concentration of peptide.
`V
`Immunology and Allergy; Kidneys and Urinary Sys
`(i) Ethanol may be used as a further solubilizing
`tem; Pharmacology; Surgery and Transplantation” 5,
`agent/solvent. The ethanol content by weight may be
`for example 2 to 5% for parenteral compositions and l
`595, (1977).
`The properties of the compositions according to the
`to 20% for oral compositions, calculated on the total
`composition.
`invention may be determined in conventional manner.
`The stability of solutions particularly against crystalli
`(ii) For a parenteral composition, an alternative fur
`ther solubilizing agent/solvent is a benzoic acid benzyl
`zation-out of the active agent may be determined using
`known tests. Tolerability of injection forms may be
`ester. This may be present at from 5 to 40% of by
`weight of the total composition.
`determined by observing the extent of bleeding and
`inflammations after injection, e.g. into thighs of rabbits
`(iii) A vegetable oil, such as olive oil or corn oil, may
`be present in both oral and parenteral compositions as
`and rhesus monkeys, and the time taken for these to
`Vehicle. The vegetable oil content by weight may be
`heal, as well as by using other usual tolerability tests.
`The absorption of the pharmacologically active pep
`‘ for example for 35 to 60%, calculated on the total com
`tide, e.g. rapid onset of a satisfactory concentration of
`position.
`-
`(iv) For emulsions for drinking, preferably agent (a)
`the peptide in the blood, and a high total absorption of
`the peptide over 24 hours, is indicated in standard tests.
`and/or (0) as defined above is present as well as a leci
`In one test a pharmaceutical composition according
`thin such as soya lecithin. Such emulsions may contain
`from 20% to 80% by weight water and contain ethanol
`to the invention is administered to rabbits, rats, dogs or_
`rhesus monkeys orally, intramuscularly or subcutane
`as a solubilizing agent/solvent.
`ously, at a dose of from 2 to 600 mg/kg animal body
`(v) For oral pellets, it is preferred to use a solid or
`weight of active peptide. Blood serum samples and
`semi-solid component (a) or (c), especially component
`45
`(0). Colloidal silicic acid, sugar, and microcrystalline
`urine samples are taken at regular intervals thereafter,
`e.g. every hour, and are analysed for the concentration
`cellulose are suitable excipients.
`of peptide therein in conventional manner.
`Compositions in accordance with the invention com
`For example the pharmacological activity in a sample
`prising a cyclosporin and a carrier comprising a compo
`nent (a) together with (i) ethanol and (iii) a vegetable oil
`may be ascertained in conventional manner according
`to known tests. In the case of cyclosporin A the effect
`as set forth above are especially advantageous in that
`of the peptide present in inhibiting lymphocyte prolifer
`they provide solutions characterised by a high degree of
`stability. In particular they exhibit markedly improved
`ation may be ascertained. Thus the blood serum is col
`stability compared with equivalent compositions in
`lected at regular intervals after administration, and is
`which one or other of the components (i) or (iii) are
`added at a concentration of from 0.3 to 10% to a mouse
`55
`in vitro spleen cell suspension in which lymphocyte
`omitted, particularly when higher concentrations of
`proliferation is induced by Concavalin A over a 72 hour
`cyclosporin (e.g. of the order of 10% and even up to
`culture period. 3-H-thymidine is then added and the
`20% by weight based on the total weight of the compo
`thymidine incorporation after 24 hours is measured to
`sition) are present. Thus on storage over longer periods
`indicate the lymphocyte proliferation.
`of time, compositions formulated with a carrier com
`prising (a) and (i) only exhibit cyclosporin precipitation
`If desired, the peptide may be administered in radio
`active form. For example in the case of the cyclospo
`at lower temperatures, e.g. at temperatures of ca. 5° C.,
`rins, in one experiment 100 mg of 3H-labelled cyclospo
`such as are commonly employed for storage of pharma
`ceuticals, e.g. in hospitals, while compositions formu
`rin 'A (prepared by cultivation of the known strain
`Tolypocladium in?atum Gams NRRL 8044 in the pres
`lated with a carrier comprising (a) and (iii) only, exhibit
`cyclosporin precipitation at both lower and elevated
`ence of methionine marked with tritium in the SCH3
`group thereof) contained in a pharmaceutical composi
`temperatures, e.g. at temperatures of from 5° up to 50°
`tion according to the invention in the form of a drinking
`C. In contrast, for compositions formulated with a car
`
`40
`
`30
`
`60
`
`65
`
`NOVARTIS EXHIBIT 2108
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`Page 4 of 6
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`

`
`7
`solution, or in a capsule, is administered perorally, or in
`the form of an injection solution is administered intra
`muscularly, to male beagle dogs. Blood samples are
`obtained from each dog every 15 minutes after adminis
`tration up to 1 hour after administration and thereafter
`every hour thereafter up to 8 hours after administration.
`The urine is collected also. Determination of the ratio
`activity in the blood and in the urine indicates the pep
`tide absorption.
`The amount of peptide to be administered in the phar
`maceutical compositions according to the invention will
`naturally depend upon the mode of administration, the
`effect desired and the condition to be treated.
`In general the amount of peptide to be administered
`in a pharmaceutical composition according to invention
`will be of the same order to that administered by the
`same route in other pharmaceutical compositions.
`In the case of the cyclosporins, the amounts to be
`administered for a therapeutically effective amount are
`well-known. When using compositions according to the
`invention a daily dose of from about 3 mg/kg to about
`50 mg/kg is indicated in order to treat chronic in?am
`mations or to provoke an immunosuppressive effect.
`The following examples illustrate the invention. All
`temperatures are in degrees Centigrade.
`
`EXAMPLE 1
`Drink Solutions
`(1a) 200 mg of cyclosporin A are dissolved on stirring
`in 1 ml of a mixture of Labra?l M 1944 CS and absolute
`ethanol (parts by weight 40:15) at 25”. 0.4 ml of olive oil
`or corn oil are added. The resultant mixture is ?ltered
`and ?lled into a small vial. The ?nal solution contains
`for every 10 parts by weight of Labra?l; ca. 3 parts by
`weight of cyclosporin A, 3 parts by weight of ethanol
`and 5 parts by weight of olive oil or corn oil.
`(1b) The composition of example (1a) may be pro
`duced on a large scale as follows:
`150.00 kg Labra?l M 1944 CS are stirred for 5 min
`utes with 50.00 kg absolute ethanol. 50.00 kg cyclospo
`rin A are then added to the mixture with stirring over a
`period of ca. 40 minutes until the cyclosporin A is com
`pletely dissolved. Ca. 212.00 kg olive oil are then added
`with stirring for ca. 10 minutes to give a total end
`weight of 462.50 kg. The obtained solution is ?ltered
`and ?lled into 50 ml containers which are then sealed, to
`give a total volume per container of 51.5 ml. As with
`any liquid composition comprising olive oil as an ingre
`dient, the means of ?ltration employed is important.
`If ?ltration is insuf?cient, and impurities, such as
`higher fatty acid ester components, present in the olive
`oil are not fully removed, these will separate out in the
`' course of l to 2 months, producing a light ground sedi
`ment. While this is not critical to utility and does not
`re?ect on the stability of the composition, ie on the
`stability of the active ingredient in the solution, for
`commercial purposes such sedimentation is preferably
`to be avoided. Suitably ?ltration for examples 1a and 1b
`is carried out by pre-?ltration using a Seitz Supra 1000
`(cellulose-Kieselguhr) layer ?lter or a Millipore
`Lifeguard CP 20 (?ber ?ass) ?lter, followed by ?ltra
`tion through a 7 pm polypropylene ?ltration cartridge,
`e.g. such as a Pall HDC BE cartridge.
`For the purposes of administration composition la or
`1b is advantageously mixed with a chocolate ?avouring
`agent, e.g. as follows:
`-
`15 g Caotina (a chocolate ?avouring agent available
`from the company Wander) are stirred into 50 ml of
`
`55
`
`60
`
`65
`
`4,388,307
`8
`milk and the desired dosage of cyclosporin A drink
`solution (7-12 ml of composition 10) are added. The
`mixture is ingested immediately.
`(1c) The following composition is obtained analo
`gously to example (la):
`
`20
`
`25
`
`40
`
`45
`
`Component
`cyclosporin A
`Labra?l M 1944 CS
`100% Ethanol
`Olive oil
`
`(a)
`(i)
`(iii)
`
`Content
`10000 mg
`300.00 mg
`100.00 mg
`ca. 425.00 mg to give an end
`volume of 1.00 ml.
`
`The compositions 1a-1c above exhibit the advantages
`of a combination of carriers (a), (i) and (iii) as hereinbe
`fore described.
`
`EXAMPLE 2
`Parenteral Forms for I.M. and SC. Administration
`100 mg of cyclosporin A are dissolved on stirring in
`a mixture of 40 mg ethanol and 0.5 ml Miglyol 812 at 25°
`C. The mixture is ?nally made up to 1 ml with Miglyol
`81.2 and ?lled under sterile conditions into an ampoule.
`The ?nal solution contains for every 10 parts by weight
`of Miglyol 812, 1 part by weight of cyclosporin A.
`EXAMPLE 3
`Parenteral Forms for I.M. and SC. Administration
`100 mg of cyclosporin A are dissolved on stirring in
`a mixture of 40 mg ethanol, 100 mg Labra?l M 1944 CS
`and 200 mg Miglyol 812 at 25°. The resulting mixture is
`made up to 1 ml with olive oil and ?lled under sterile
`conditions into an ampoule.
`The ?nal solution contains for every 10 parts by
`weight of Miglyol 812, 5 parts by weight each of cyclos
`porin A and Labra?l and 25 parts by weight of olive oil.
`
`EXAMPLE 4
`Parenteral Form for I.M. and SC. Administration
`200 mg of cyclosporin A are dissolved in a mixture of
`400 mg benzoic acid benzyl ester and 0.3 ml Miglyol
`812 at 25°. The resultant mixture is made up to 1 ml
`with Miglyol 812 and ?lled under sterile conditions into
`an ampoule.
`The ?nal solution contains for every 10 parts by
`weight of Miglyol 812, 6 parts by weight of cyclosporin
`A.
`
`EXAMPLE 5
`Parenteral Form for I.M. and SC. Administration
`200 mg of cyclosporin A are dissolved on stirring in
`a mixture of 50 mg ethanol, 300 mg Labra?l M 1944 CS
`and 0.3 ml Miglyol 812 at 25°. The resultant solution is
`made up to 1 ml with Miglyol 812 and ?lled under
`sterile conditions into an ampoule.
`The ?nal solution contains for every 10 parts by
`weight of Miglyol 812, 7 parts by weight of Labra?l and
`5 parts by weight of cyclosporin A.
`EXAMPLE 6
`Capsules for Oral Administration
`200 mg of cyclosporin A are dissolved on stirring in
`a mixture of 600 mg Glycerol mono-oleate and 30 mg
`ethanol at 30°. The ?nal solution is encapsulated in a
`soft gelatine capsule.
`
`NOVARTIS EXHIBIT 2108
`Par v Novartis, IPR 2016-00084
`Page 5 of 6
`
`

`
`What we claim is:
`1. A liquid pharmaceutical composition comprising a
`pharmaceutically effective amount of a cyclosporin and
`a carrier comprising the following components:
`(a) a trans-esteri?cation product of a natural vegeta
`ble oil triglyceride and a polyalkylene polyol;
`(b) a vegetable oil; and
`(0) ethanol; whrein the ratio of component (a) to
`cyclosporin is 10:02 to 10 parts by weight; the
`amount of component (b) is 35 to 60% by weight‘
`based on the total weight of the composition, and
`the amount of component (0) is l to 20% by weight
`based on the total weight of the composition.
`2. Composition according to claim 1, wherein the
`cyclosporin is cyclosporin A.
`3. Composition according to claim 1, wherein the
`cyclosporin is dihydrocyclosporin C.
`4. Composition according to claim 1, wherein the
`cyclosporin is cyclosporin D.
`'
`5. Composition according to claim 1, wherein the
`cyclosporin is dihydrocyclosporin D.
`6. Composition according to claim 1, wherein compo
`nent (a) is a trans-esteri?cation product of two molar
`parts of a natural vegetable oil triglyceride and one
`molar part of a polyethylene glycol of MW 200 to 800.
`7. Composition according to claim 6, wherein the
`natural vegetable oil is kernel oil.
`8. Composition according to claim 7, wherein compo
`nent (a) is a polyoxyethylated kernel oil mixture, having
`a density of D2°=0.940-0.965, an acid number <2, an
`iodine number=60-90, a saponi?cation number=1
`
`(H.L.B.)=4.
`
`’
`
`_
`
`9. Composition according to claim 1, wherein compo
`nent (b) is olive oil or corn oil.
`10; Composition according to claim 9, wherein com
`ponent (b) is olive oil.
`11. Composition according to claim 1, wherein the
`ratio of component (a) to cyclosporin is 10:1 to 10 parts
`by weight.
`. 12. Composition according to claim 11, wherein the
`ratio is 10:1 to 7 parts by weight.
`13. Composition according to claim 1, wherein com
`ponents (b) and (0) together are present in an amount of
`up to 60% by weight based on the total weight of the
`composition.
`>
`14. Composition according to claim 1, formulated as
`solution for oral administration.
`.
`_
`15. A liquid pharmaceutical composition comprising
`a pharmaceutically effective amount of a cyclosporin
`and a carrier comprising the following components: ,
`(a) a trans-esteri?cation product of a hydrogenated
`vegetable oil triglyceride and a polyalkylene
`polyol;
`-
`(b) a vegetable oil; and
`(0) ethanol;
`wherein the ratio of component (a) to cyclosporin is
`10:0.2 to 10 parts by weight; the amount of component
`(b) is 35 to 60% by weight based on the total weight of
`the composition, and the amount of component (0) is l
`to 20% by weight based on the total weight of the
`composition.
`
`9
`
`4,388,307
`.45-175
`
`and
`
`a
`
`10
`hydrophilic-lipophilic
`
`balance
`
`15
`
`* * i It
`
`9
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`NOVARTIS EXHIBIT 2108
`Par v Novartis, IPR 2016-00084
`Page 6 of 6