`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 7 2
`
`(11) International Publication Number:
`
`WO 00/51593
`
`A61K 31/167, 9/00, 9/12
`
`A2
`
`_
`_
`
`
`(43) International Publication Date: 8 September 2000 (08.09.00)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`,
`
`(30) Priority Data:
`9904629.4
`
`2 Match 1999 (02.03.99)
`
`PCT/GBOO/OO664
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, BE,
`24 February 2000 (24.02.00)
`ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP,
`
`KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`
`MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU,
`SD, SE, SG, 31» SK, SL, TJ, TM, TR, TT, TZ, UA, UG,
`GB
`US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE,
`
`LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM,
`
`AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT,
`(71) Applicant (for all designated States except US): WEST PHAR-
`BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU,
`
`MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM,
`MACEUTICAL SERVICES DRUG DELIVERY & CLIN—
`ICAL RESEARCH CENTRE LIMITED [GB/GB]; Albert
`GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Einstein Centre, Nottingham Science & Technology Park,
`
`University Boulevard, Nottingham NG7 2TN (GB).
`Published
`
`(72) Inventors; and
`Without international search report and to be republished
`(75) Inventors/Applicants (for US only): WA'ITS, Peter [GB/GB];
`upon receipt of that report.
`
`31 Lindale Close, Gamston, Nottingham NG2 6PU (GB).
`LAFFERTY, Ian [GB/GB]; 28 Nanpantan Road, Loughbor-
`
`ough, Leicestershire LE11 3SU (GB).
`
`(74) Agent: DEE, Ian, M.; Eric Potter Clarkson, Park View House,
`58 The Ropewalk, Nottingham NG1 SDD (GB).
`
`
`
`(54) Title: ORAL DRUG DELIVERY SYSTEM
`
`(57) Abstract
`
`An oral drug delivery composition that dissolves rapidly in the mouth, which comprises on a solid foam formed from a protein.
`
`
`
`
`
`

`

`
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`
`{EEQ
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`can: d’Ivoirc
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`
`
`

`

`wo 06/51593
`
`PCT/GB00/00664
`
`Oral Drug Delivery System
`
`The present invention relates generally to the oral administration of drugs
`
`using a delivery system in the form of a solid foam that dissolves rapidly
`
`in the mouth, has excellent mouth—feel and is suitable for taste masking.
`
`More specifically,
`
`the present
`
`invention relates to an oral delivery
`
`composition comprising a therapeutic agent and a solid foam formed from
`
`a protein.
`
`The administration of drugs via the mouth (oral administration) using
`
`solid dosage forms such as tablets and capsules remains the most popular
`
`means of dosing drugs. However,
`
`in certain situations, such as the
`
`treatment of children,
`
`the elderly or where a rapid onset of action is
`
`required, the use of dosage forms that dissolve rapidly in the mouth can
`
`be advantageous.
`
`Different formulations and formulation methods have been developed to
`
`accelerate the disintegration and dissolution rate of conventional
`
`tablet
`
`systems. These have included polyethylene glycol blends,
`
`freeze—dried
`
`products and fast dissolving excipients.
`
`Fast dissolving dosage forms for oral delivery have been reviewed by
`
`Rathbone et al. (Chapter 11 in Oral mucosal drug delivery, Ed. Rathbone,
`
`Dekker, New York, 1996).
`
`A variety of fast dissolving oral products has been described in the prior
`
`art.
`
`Freeze-dried systems in the form of lyophilized tablets (Lyocs“’)
`
`were first reported in 1978. A well known example is described in GB-A—
`
`1,548,022 this system comprises a network of the active ingredient and a
`
`water soluble or water dispersible carrier. The network is obtained by
`
`

`

`WO 00/51593
`
`PCT/GB00/00664
`
`sublimating a solvent from a composition in the solid state. Another
`
`freeze dried system is Zydis 7“ which is available from Scherer DDS,
`
`Swindon. ZydisTM has been reviewed by Seager (J. Pharm. , Pharmac, E,
`
`375, 1998).
`
`Other examples of formulations that are intended to dissolve rapidly in the
`
`mouth can be found in the prior art. US-A—4,855,326 describes a melt
`
`spinnable carrier, such as a sugar, which is combined with an active
`
`ingredient and the resulting mixture spun into a "candyfloss" preparation.
`
`The spun "candy-floss" product
`
`is
`
`then compressed into a rapidly
`
`dispersing, highly porous solid dosage form.
`
`US-A-5,120,549 describes a fast-dispersing matrix system. The system is
`
`prepared by first solidifying a matrix-forming system dispersed in a first
`
`solvent and subsequently contacting the solidified matrix with a second
`
`solvent that is substantially miscible with the first solvent at a temperature
`
`lower than the solidification point of the first solvent, the matrix-forming
`
`elements and active ingredient being substantially insoluble in the second
`
`solvent, whereby the first solvent is substantially removed resulting in a
`
`fast-dispersing matrix.
`
`US-A-5,178,878 describes
`
`tablets comprising microparticles and an
`
`effervescent disintegrating agent. The microparticles contain an active
`
`pharmaceutical ingredient which is encompassed by a protective coating.
`
`On contact with saliva,
`
`the
`
`effervescent
`
`agent
`
`results
`
`in rapid
`
`disintegration of the tablet and release of the microparticles.
`
`US—A-5,298,261 describes fast-dispersing dosage forms which comprise a
`
`partially collapsed matrix network that has been vacuum—dried above the
`
`

`

`WO 00/51593
`
`PCT/GB00/00664
`
`collapse temperature of the matrix. However, the matrix is preferably at
`
`least partially dried below the equilibrium freezing point of the matrix.
`
`US—A—5,587,180 describes a particulate support matrix for a tablet and
`
`method for making same, which disintegrates or dissolves in just a few
`
`seconds once placed in the oral cavity. The particulate support matrix
`
`comprises a first polymeric component which may be a polypeptide, a
`
`second polymeric component which may be a different polypeptide, and
`
`may be a hydrolyzed gelatin, and a bulking agent.
`
`US—A-5,609,883 describes the manufacture of a fast dissolving tablet
`
`using standard machinery. These tablets comprise 50% or greater of
`
`carbohydrate and alcohol as a lubricant.
`
`W094/ 11438 describes fast-dispersing dosage forms of very low density
`
`formed by gelling, with agar, aqueous systems containing the matrix-
`
`forrning elements and active ingredient, and then removing water by
`
`forced air, vacuum drying, or other drying systems.
`
`JP-A—9216816 describes a highly water soluble solid, fast dissolving tablet
`
`produced by kneading lactilcol with water and compressing.
`
`JP—A-9071523 describes tablets with rapid disintegration in the oral
`
`cavity.
`
`These
`
`are prepared with
`
`active,
`
`crystalline
`
`cellulose,
`
`hydroxypropyl cellulose and a lubricant.
`
`Crystalline cellulose and
`
`hydroxypropyl cellulose are used in a ratio of 1:2.
`
`EP-A—481,294 describes a rapid dissolving tablet containing a high
`
`concentration (50% w/w) of cysteine derivatives, cellulose derivatives and
`
`sugars.
`
`

`

`W0 Oil/51593
`
`PCT/GBOO/00664
`
`EP—A—711,547 describes tablets for rapid dissolution in the mouth. These
`
`are prepared by direct compression of an uncured matrix together with an
`
`enhancer or binder and a controlled release system.
`
`EP-A-553,777 describes fast dissolving tablets prepared by compression
`
`moulding of an active ingredient, a carbohydrate and enough water or
`
`water alcohol to wet the carbohydrate.
`
`EP-A-590,963 describes the preparation of tablets by filling a mould with
`
`a wet paste and moulding the paste under compression.
`
`W091/04747 describes an effervescent dosage form comprising an
`
`effervescent
`
`agent
`
`for
`
`rapid
`
`disintegration
`
`and
`
`a
`
`plurality
`
`of
`
`microcapsules, said microcapsules including at
`
`least one systemically
`
`distributable pharmaceutical
`
`ingredient and an encapsulant substantially
`
`surrounding the pharmaceutical ingredient.
`
`WO96/02237 describes instant dissolution solid pharmaceuticals which
`
`comprise an active material coated with a water-dispersible binder, a
`
`cellulose expanding agent, a water soluble polyol and a diluent.
`
`WO97/38679 describes a fast disintegrating solid oral dosage form
`
`comprising an active substance, a filler, and a binder. The dosage forms
`
`are prepared by making a suspension or solution of the ingredients, filling
`
`into a mould and removing the solvents without freeze drying.
`
`Foams have not been widely used for the administration of drugs. Rectal
`
`foams for the delivery of steroids for the treatment of colonic disease are
`
`known. Sciarra (Modern Pharmaceutics, 3rd edition, editors - Banker and
`
`

`

`W0 Oil/51593
`
`PCT/GB00/00664
`
`Rhodes, Dekker, New York, 1996) describes quick—breaking liquid foams
`
`and mentions that it
`
`is possible to formulate edible foams to disperse
`
`cough remedies, calcium supplements, antacids, vitamins and other
`similar products. Sciarra also suggests that these systems may be readily
`
`acceptable to children and the geriatric population.
`
`US-A-5,079,018 describes a fast—dispersing dosage form which comprises
`
`a porous skeletal structure of a water soluble, hydratable gel or foam
`
`forming material that has been hydrated with water and rigidified in the
`
`hydrated state with a rigidifying agent. The foam forming material can be
`
`gelatin,
`
`albumin or
`
`lecithin and is
`
`rigidified with a mono— or
`
`polysaccharide. The dosage form can be formulated as wafers,
`
`tablets,
`
`granules and powders. The dehydration process is performed using a
`
`liquid organic solvent at a temperature of about 0°C or below. Ethanol is
`
`a preferred organic solvent.
`
`Dickenson (An Introduction to Food Colloids, Oxford University Press,
`
`Oxford, 1992, p25) has reviewed the preparation and stabilization of food
`
`colloids.
`
`Stable foams are known to be difficult
`
`to produce because
`
`bubbles are susceptible to fast drainage and rupture. Moreover, diffusion
`
`of gas from small bubbles into big bubbles can proceed quickly in the
`
`absence of a stabilizing film of a polymeric material. Stability can be
`
`provided by an insoluble adsorbed layer of a coagulated protein such as
`
`egg-White or by converting a liquid foam into a solid foam through, for
`
`example, heat treatment.
`
`Egg-white is known to be an effective foaming agent in foods. This effect
`
`arises from the different constituents in egg-white that are important in
`
`stabilizing a liquid foam as well as the conversion of the liquid foam into
`
`a solid foam during heating.
`
`The major component of egg-white is
`
`

`

`W0 Oil/51593
`
`PCT/GB00/00664
`
`ovalbumin, which is an effective foam stabilizer. However, the presence
`
`of highly surface active globulins can provide foam with small bubbles
`
`and a smooth texture (Dickenson, An Introduction to Food Colloids,
`
`Oxford University Press, Oxford,
`
`1992, p135).
`
`Ovomucoid is
`
`particularly useful in this regard. Lysosyme is another component of egg-
`
`white which can increase film strength and enhance foam stability.
`
`Dickenson has stated that co-operative protein-protein interaction between
`
`basic protein (e.g.
`
`lysosyme) and acidic egg—white proteins are largely
`
`electrostatic. Hence in foam stabilization,
`
`the interaction of a cationic
`
`polymer with an anionic polymer can be used to form an interfacial
`
`complex. For example,
`
`two proteins of opposite charge will provide a
`
`means of enhancing foam stability. Examples are beta—lactoglobulin and
`
`bovine serum albumin.
`
`In producing a solid foam for pharmaceutical use,
`
`sugar can be added. Sucrose, fructose, glucose, mannitol, sorbitol can all
`
`be employed.
`
`The present invention provides an oral delivery composition comprising a
`
`therapeutic agent and a solid foam formed from a protein. Typically the
`
`oral delivery composition of
`
`the invention is
`
`a rapidly dissolving
`
`composition.
`
`By rapidly dissolving composition we mean a composition having a
`weight of from 0.1 gram to 10 gram that will dissolve in the mouth in the
`
`presence of saliva in less than 300 seconds.
`
`It
`
`is preferred that the
`
`composition will dissolve in the mouth in less than 150 seconds and it is
`
`especially preferred that the composition will dissolve in less than 60
`
`seconds.
`
`

`

`wo 0'0/51593
`
`PCT/GBOO/00664
`
`The composition of the invention dissolves rapidly in the mouth to release
`
`the therapeutic agent.
`
`Albumins are foam forming proteins which are suitable for use in the
`
`present invention. A preferred albumin is egg albumin. Ovalbumin or
`
`egg-white is particularly preferred.
`
`The therapeutic agent may be a drug, an antigen or a vaccine.
`
`Drugs suitable for use in the present invention include, but are not limited
`
`to, drugs acting on the central nervous system, drugs acting on the
`
`gastrointestinal tract, drugs acting on the cardiovascular system, antibiotic
`
`drugs, vitamins, vaccines, nutrients, drugs
`
`for analgesia, drugs
`
`for
`
`erectile dysfunction, hormones such as insulin, calcitonin, parathyroid
`
`hormone, nicotine for
`
`smoking cessation,
`
`antitussive agents,
`
`local
`
`anaesthetics, antiemetics, anticonvulsants, sedatives, sleep induction.
`
`Drugs that are preferred for use in the present
`
`invention include
`
`paracetamol,
`
`ibuprofen, nicotine, piroxicam, enalapril, apomorphine,
`
`codeine, buprenorphine and combinations of such drugs. An especially
`
`preferred drug is paracetamol.
`
`Antigens suitable for use in the present invention include, but are not
`
`limited to, allergen antigens, tetanus toxoid, polio myelitis, haemodulius
`
`influenzae.
`
`The amount of therapeutic agent present
`
`in the compositions of the
`
`invention is not especially limited and will depend on several factors
`
`which will be readily apparent to the person of ordinary skill in the art
`
`such of the nature and intended purpose of the therapeutic agent. The
`
`

`

`wo (lb/51593
`
`PCT/GBOO/00664
`
`dose of the therapeutic agent is typically from 0.1% w/w to 90% w/w (as
`
`measured in the dry foam). The therapeutic agent is generally present in
`an amount of at least 1% w/w, for-example 1% w/w to 80% w/w. A
`
`preferred dose of the therapeutic agent is from 2.5% w/w to 75% w/w
`
`and an especially preferred dose of the therapeutic agent is from 5% w/w
`
`to 70% w/w, particularly 5% w/w to 50% w/w.
`
`The compositions may also include a polysaccharide.
`
`Polysaccharides
`
`stabilise the foam, enhance volume development and improve handling.
`
`Polysaccharides suitable for use in the compositions of the invention
`
`include sucrose, for example powdered sucrose (icing sugar) or castor
`
`sugar (both available from Tate and Lyle), mannitol, sorbitol,
`
`lactose,
`
`fructose
`
`and xylitol
`
`(Sigma). Another
`
`suitable polysaccharide
`
`is
`
`carboxymethyl cellulose (CM) which has a high viscosity and a high
`
`degree of substitution.
`
`If the compositions of the invention contain a polysaccharide the protein
`
`and polysaccharide are together typically present in an amount of from
`
`10% w/w to 99.9% w/w (as measured in the dry foam), generally less
`
`than 99% w/w, for example 20% w/w to 99% w/w. A preferred amount
`
`of protein and polysaccharide is 25% w/w to 97.5% w/w, an especially
`
`preferred amount is 30% w/w to 95% w/w, particularly 95% w/w to 50%
`
`w/w.
`
`When the compositions of the invention contain a polysaccharide the ratio
`
`of protein to polysaccharide is typically from 1:1 to 1:10, preferably from
`
`1:4 to 1:8.
`
`

`

`WO 00/51593
`
`PCT/GB00/00664
`
`Of course, if the compositions do not contain a polysaccharide the protein
`
`may represent a greater proportion of the total weight of the compositions.
`
`In this case, the amount of protein may be from 1% w/w to 99.9% w/w,
`
`generally from 1% w/w to 90% w/w (as measured in the final dried
`
`foam). A preferred amount of protein is from 15 % w/w to 80% w/w and
`
`an especially preferred amount of protein is from 10 to 50% w/w.
`
`The compositions may also include a non-ionic surfactant. Non-ionic
`
`surfactants effect the structure of the foam stabilising layer. The effect
`
`will depend on the composition of the film, but could be an increase in
`
`foam volume or an increase in foam density. Non-ionic surfactants
`
`suitable for use in the present invention include polysorbates (commonly
`
`known as “Tweens”, ICI Chemicals).
`
`The compositions may also include other pharmaceutically acceptable
`
`ingredients such as sweeteners, flavouring agents, taste masking agent for
`
`drugs that have a bitter taste. A suitable taste masking agent is Eudragit
`
`E100® (Registered Trade Mark of Rohm Pharma, Dannstradt, Germany).
`
`The inclusion of sugars such as sucrose will also help mask any bitter
`
`taste. The compositions may also contain pharmaceutically acceptable
`
`colourants.
`
`Suitable sweeteners include saccharin (Sigma) and aspartame. Suitable
`
`flavourings include orange, lemon, raspberry and peppermint.
`
`Components such as sweeteners and flavourings, if present, are typically
`
`present in the formulations of the invention in an amount of from 0.1 to
`
`1% by weight each.
`
`

`

`WO 00/51593
`
`PCT/GBOO/00664
`
`The compositions of the invention can be prepared by incorporating the
`
`therapeutic agent into the foam before the foam is solidified.
`
`Suitable
`
`solidifying methods include heat treatment, freeze drying and vacuum
`
`drying.
`
`The compositions of the invention may be prepared by first whisking the
`
`protein,
`
`for example egg-white or ovalbumin, using a food mixer or
`
`similar equipment until a stiff foam has been produced. The therapeutic
`
`agent is typically mixed with other excipients such as sugars, artificial
`sweeteners, and flavouring agents. This powder is gently mixed (folded)
`
`into the foam.
`
`The therapeutic agent can also be taste masked by
`
`dissolving a taste masker, for example Eudragit E100 in a suitable solvent
`
`and adding this solution dropwise to the powder containing the therapeutic
`
`agent and granulating the mixture. Suitable solvents for the taste masker
`
`include
`
`dichloromethane,
`
`a
`
`water/ethanol mixture
`
`and
`
`an
`
`acetone/isopropanol mixture. After drying the granules these can be
`
`mixed with the foam. Typically,
`
`the mixture is then distributed into
`
`moulds and dried. Suitable drying methods include heating in an oven
`
`(which may be done at atmospheric pressure or under reduced pressure),
`
`microwaving or freeze drying.
`
`Alternatively,
`
`the therapeutic agent and any other excipients such as
`
`sugars, artificial sweeteners, flavouring agents and a taste masker can be
`
`mixed with the protein, for example egg-white or ovalbumin, and then the
`
`mixture whisked using a food mixer or similar equipment to produce a
`
`stiff foam. If a taste masker is used it is typically added to the therapeutic
`
`agent and other excipients as described above.
`
`The foams can be moulded or further modified by known pharmaceutical
`
`processes such as grinding and compression.
`
`10
`
`

`

`WO 00/51593
`
`PCT/GB00/00664
`
`When producing a foam from egg-white, the pH may be reduced towards
`
`the isoelectric points of acidic egg-white proteins. Suitable agents for the
`
`adjustment of pH include acetic acid, citric acid, tartaric acid, succinic
`
`acid and potassium acid tartrate.
`
`The present invention is now illustrated but not limited by reference to the
`
`following Examples.
`
`Example 1 General method for the preparation of a solid foam product
`
`Egg-white or reconstituted dried egg—white (ovalbumin) (obtained from
`
`Sigma, Poole, UK and Cake Art Ltd, Somerset, UK, respectively) was
`
`mixed with water using a food mixer on medium speed until a stiff foam
`
`(meringue) was formed. The drug was blended with other excipients such
`
`as various carbohydrates (sugars), sweeteners and flavouring agents using
`
`mortar and pestle and then gently mixed (folded) into the foam using a
`
`spatula. Portions (approximately 1 g) of the drug-containing foam were
`
`then filled into small moulds (5 ml weighing boats) and placed in an oven
`
`(Mexcel General Purpose Oven) overnight at 60°C (temperatures of 40 to
`
`80°C can also be used) to produce a solid foam.
`
`A typical formulation is as follows: -
`
`Dried egg-white
`
`7.5 g (approximately equal to one egg—white)
`
`Water
`
`"Sugar"
`
`35 ml
`
`45 g (30 to 60 g were used)
`
`Drug (if paracetamol)
`
`up to 20 g (5 to 20 g were used)
`
`Flavouring
`
`0.5 g
`
`11
`
`

`

`WO 00/51593
`
`PCT/GBOO/00664
`
`Sweetener
`
`0.5 g (both flavouring and sweetener could be
`
`included in greater or smaller amounts)
`
`Formulations
`
`containing orange,
`
`lemon raspberry and peppermint
`
`flavourings were prepared.
`
`Formulations containing saccharin and aspartame as sweeteners were
`
`prepared.
`
`Example 2 A solid foam containing paracetamol produced using sucrose
`
`in the form of castor sugar (formulation A)
`
`10 g of paracetamol and 55 g of castor sugar was slowly folded into an
`
`egg-white foam as described in Example 1. A solid foam was prepared as
`
`described in Example 1.
`
`Example 3 A solid foam containing paracetamol produced using
`
`sucrose in the form of icing sugar (formulation B)
`
`10 g of paracetamol and 55 g of icing sugar was slowly folded into an
`
`egg-white foam as described in Example 1. A solid foam was prepared as
`
`described in Example 1.
`
`Example 4 A solid foam containing paracetamol and orange flavour
`
`(formulation C)
`
`10 g of paracetamol, 55 g of icing sugar and 0.25 g of orange flavouring
`
`were mixed in a mortar and pestle. This was then folded into one beaten
`
`egg-white and weighed into small tablet sized portions and converted into
`
`a solid foam by treating portions as described in Example 1.
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`wo 00/51593
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`PCT/GBOO/00664
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`Example 5 A solid
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`foam containing
`
`paracetamol,
`
`flavour
`
`and
`
`sweetening agent (formulation D)
`
`10 g of paracetamol, 45 g of icing sugar, 0.5 g orange flavouring, 0.5 g
`
`saccharin were mixed in a mortar and pestle. This was then folded into
`
`one beaten egg—white and then processed as in Example 4.
`
`Example 6 A solid foam with a peppermint flavour (formulation E)
`
`A solid foam was produced as in Example 5, but 0.75 g of peppermint oil
`
`was used instead of 0.5 g orange flavour.
`
`Example 7 A solid foam with a peppermint flavour (formulation F)
`
`A solid foam was prepared as described in Example 6, but 1.25 g of
`
`peppermint flavour was used.
`
`Example 8 A solid foam prepared using mannitol (formulation G)
`
`A solid foam was prepared as in Example 6, but mannitol was used
`
`instead of icing sugar.
`
`Example 9 A solid foam prepared using mannitol (formulation H)
`
`A formulation as described in Example 8 was prepared but with 1.25 g of
`
`peppermint flavour.
`
`Example 10 Preparation of solid foams using freeze drying
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`WO 00/51593
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`PCT/GB00/00664
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`Foams as described in Examples 1
`
`to 9 were prepared using a freeze
`
`drying process.
`
`Freeze drying was performed by freezing the foam
`
`meringues in an -80°C freezer for approximately 4 hours. The foams
`
`were then transferred to an Edwards bench top freeze-drier and dried
`
`overnight.
`
`Example 11 Preparation of solid foams using vacuum drying
`
`Foams as described in Examples 1—9 were prepared using a vacuum
`
`drying process.
`
`The vacuum drying was performed using a Virtis Genesis freeze-drier
`
`(without engaging the freezer). Samples were placed in the drier at 35°C
`
`and the vacuum set to a pressure of 300 Pa.
`
`Example 12 Solid foam with the addition of a polymer to provide taste
`
`masking
`
`Paracetamol 20 g, icing sugar 55 g, orange flavouring 0.5 g were mixed
`
`together in a mortar and pestle. 10 grams Eudragit E100 was dissolved in
`
`a mixture of 4 g water and 66 g ethanol was added dropwise to the
`
`paracetamol blend with constant mixing (spatula) until a satisfactory
`
`granulation was achieved. The granules were wet screened (1.4 mm
`
`sieve) dried at 40°C for 4 hours in an oven and then blended with the
`
`foam prepared as described above in Example 1. Portions (approximately
`
`1 g) were dried in an oven and in the freezer-drier as previously described
`
`to produce solid foams. A reduction in aftertaste was achieved when
`
`evaluated in a group of volunteers.
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`14
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`WO 00/51593
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`Example 13 Further examples of solid foams containing paracetamol
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`(formulations I, J and K)
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`As in Example 1 using, dried egg-white, 15 g reconstituted with water 75
`
`ml,
`
`to form the foam.
`
`Paracetamol 20 g,
`
`icing sugar 55 g and
`
`approximately 1 ml of orange (formulation I), lemon (formulation J) and
`
`peppermint liquid flavourings (formulation K), were mixed (mortar and
`
`pestle) and gradually added to the foam. The mixture was dried in an
`
`oven at 60°C overnight.
`
`Example 14 Use of Eudragit E100 as a binder to aid taste masking
`
`(formulations L1 and L2)
`
`A solution containing Eudragit E100 30 g in dichloromethane 100 ml was
`
`prepared.
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`Paracetamol 10 g,
`
`icing sugar 10 g, orange flavouring 0.1 g and
`
`aspartame 0.2 g were mixed together (mortar and pestle) and "granulated"
`
`with 6.7 ml of the Eudragit solution (= 2 g of polymer). The mixture
`
`rapidly dried in air and was passed through a 0.5 mm sieve.
`
`The granules 13.6 g,
`
`icing sugar 16 g orange flavouring 0.09 g and
`
`aspartame 0.1 g were blended together using a Turbula mixer for 5
`
`minutes.
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`Dried egg-white 3 g was reconstituted with 15 ml of water and whisked
`
`until a stiff foam had formed. The powder blend was then gradually
`
`added to the meringue.
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`15
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`W0 Oil/51593
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`PCT/GB00/00664
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`Portions were placed in moulds (weighing boats) and dried in an oven at
`
`60°C overnight (formulation Ll).
`
`Portions were frozen (—80°C) and dried in freeze drier overnight
`
`(formulation L2).
`
`Example 15 Use of Eudragit E100 as a binder (formulations M1 and M2)
`
`These formulations were made as for formulation L but using 3.3 ml of
`
`Eudragit/dichloromethane solution (1 g of polymer).
`
`Oven dried
`
`formulations were labelled M1 and freeze dried formulations were
`
`labelled M2.
`
`Example 16 Use of Beta-cyclodextrin for taste masking (formulation N)
`
`3 g dried egg white was reconstituted with 15 ml of water and whisked
`
`into a stiff foam as in example 1. Paracetamol 6 g, Beta-cyclodextrin
`
`(Sigma) 5 g, icing-sugar 17 g, a lemon flavouring 0.15 g, aspartame 0.22
`
`g were dry mixed in a Turbula mixer for 5 minutes. The powder blend
`
`was then incorporated into the foam.
`
`2 g portions were placed in the
`
`moulds (weighing boats) and the meringue dried in an oven at 40°C
`
`overnight.
`
`Example 17 Flavoured product (formulation 0)
`
`Approximately 2 ml of liquid lemon flavour was added to formulation J of
`
`Example 13 (post manufacture) and allowed to dry in air for 1 hour.
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`Example 18 Use of xylitol in foam preparation (formulation P)
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`16
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`The foam was prepared as before as in example 1. To one quarter portion
`
`(equivalent to 3.75 g dried egg-white and 18.75 ml water) xylitol 13 g,
`
`icing sugar 13 g, paracetamol 10 g and aspartame 0.5 g were gradually
`
`added. The product was dried in over at 60°C overnight.
`
`Example 19 Use of xylitol in foam preparation (formulation Q)
`
`The foam was prepared as for formulation P (example 18) but 26 g of
`
`xylitol was added and the icing sugar was removed.
`
`Example 20 Evaluation of solid foams by taste testing in volunteers
`
`The properties of paracetamol containing solid foams as described in
`
`formulations A to 0 were evaluated in a group of volunteers (n=6). The
`
`time for the formulation to dissolve (melt) in the mouth and the taste and
`
`aftertaste were recorded. Details are given in Table 1. The taste and
`
`aftertaste were ranked according to a scale from 1 to 5.
`
`Table 1
`
`Evaluation of solid foams containing paracetamol
`
`Formulation Melt
`
`in mouth
`
`time (sec)
`
`01
`
`Taste*
`
`After taste
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`20/30
`
`2 chewy
`
`2 gritty/OK
`
`2 gritty/OK
`
`3 slight
`
`3 slight
`
`3 slight
`
`
`
`2 gritty/minty/OK
`
`3 slight
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`W0 Oil/51593
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`PCT/GBOO/00664
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`4 very slight
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`4 good melt
`
`4 very slight
`
`4 good melt
`
`4 good melt
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Q
`
`* Formulation Key
`
`A
`
`B
`
`C
`
`D
`
`E
`
`F
`
`Castor sugar or sucrose/paracetamol
`
`Icing sugar/paracetamol
`
`Icing sugar/paracetamol/orange
`
`Granulation/paracetamollorange
`
`Granulation/paracetamol x 2/peppermint
`
`Granulation/paracetamol x 2/extra peppermint
`
`G Mannitol granulation/paracetamol x 2/pepperrnint
`
`H Mannitol granulation/paracetamol x 2/extra peppermint
`
`I
`
`J
`
`Icing sugar/paracetamol/orange solution
`
`Icing sugar/paracetamol/lemon solution
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`18
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`

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`W0 (IO/51593
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`PCT/GB00/00664
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`K
`
`Icing sugar/paracetamol/peppermint solution
`
`ozzw
`
`"U
`
`Icing sugar/paracetamol/orange/Eudragit E100 (2 g)
`
`Icing sugar/paracetamol/orange/Eudragit E100 (1 g)
`
`Icing sugar/paracetamol/1emon/Beta—cyclodextrin/aspartame
`
`Icing sugar/paracetamol/lemon solution/post manufacture lemon
`solution
`
`Icing sugar/xylitol/paracetamol/aspartame
`
`Q
`
`Xylitol/paracetamol/aspartame
`
`* Taste Key
`
`1
`
`2
`
`3
`
`4
`
`5
`
`Very poor
`
`Poor
`
`Average
`
`Good
`
`Excellent
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`WO 00/51593
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`Claims
`
`PCT/GB00/00664
`
`1.
`
`An oral delivery composition comprising a therapeutic agent and a
`
`solid foam formed from a protein.
`
`2.
`
`A composition according to Claim 1, wherein the protein is an
`
`albumin.
`
`3.
`
`A composition according to Claim 2, wherein the albumin is egg-
`
`albumin.
`
`4.
`
`A composition according to Claim 3, wherein the albumin is
`
`ovalbumin or egg-white.
`
`5.
`
`A composition according to any one of Claims 1 to 4 which further
`
`comprises a polysaccharide.
`
`6.
`
`A composition according to Claim 5, wherein the polysaccharide is
`
`sucrose, powdered sucrose (icing sugar), castor sugar, mannitol, sorbitol,
`
`lactose, fructose, xylitol or carboxymethyl cellulose (CMC).
`
`7.
`
`A composition according to any one of Claims 1
`
`to 6 which
`
`dissolves in the mouth in less than 60 seconds.
`
`8.
`
`A composition according to any one of Claims 1 to 7 which further
`
`comprise a flavouring agent.
`
`9.
`
`A composition according to any one of Claims 1 to 8 which further
`
`comprises a taste masking agent.
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`20
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`W0 Oil/51593
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`10.
`
`A composition according to any one of Claims 1 to 9 wherein the
`
`therapeutic agent is a drug, an antigen or a vaccine.
`
`11.
`
`A composition according to Claim 10, wherein the drug is
`
`paracetamol.
`
`12.
`
`A composition according to Claim 10, wherein the drug is selected
`
`from the group codeine,
`
`ibuprofen, piroxicam, enalapril, apomorphine,
`
`nicotine, buprenorphine and combinations thereof.
`
`13.
`
`A method for the preparation of a composition according to any
`
`one of Claims 1
`
`to 12 comprising a heating, freeze-drying or vacuum
`
`drying step.
`
`14.
`
`The use of a solid foam formed from a protein for the oral delivery
`
`of a drug, a vaccine or another therapeutic agent.
`
`15.
`
`A composition comprising a therapeutic agent and a solid foam
`
`formed from a protein for use as a medicament.
`
`16.
`
`The use of a foam formed from a protein in the manufacture of a
`
`composition which is adapted for oral delivery of a therapeutic agent.
`
`21
`
`