CA2352178A1 - Phospholipid compositions - Google Patents

Abstract

The present invention relates to the preparation of powder or solid compositions comprising single and double chain amphiphilic lipids in association with polymers which harden them so that they can be comminuted into powder or granules. The compositions can act as carriers for biological ly active compounds and can be administered to living organisms. Such a composition may comprise a biologically active compound and monoacyl and diacyl membrane lipid in association with a polymer, said composition being a solid that when stored in a glass container remains free flowing after 3 months at 40 ~C and 75 % relative humidity. The lipids may be selected from those which have GRAS status e.g. enzyme modified lecithin, and the polymer may be selected from natural polysaccharide polymers, starches and their derivatives, cellulose and its derivatives and gelatines.

Description

PHOSPHOLIPID COMPOSITIONS
Field of the invention The present invention relates to the preparation of powder or solid compositions comprising single and doable chain amphiphilic lipids generally.
It particularly relates to lipid compositions comprising monoacyl and diacyl membrane lipid in association with polymers and biologically active compounds for administration to a living organism. Specifically, it describes the preparation of novel lipid polymer compositions that have improved physical characteristics and higher loading capacity for Iipophilic and hydrophilic compounds. More specifically, it relates to stable membrane Lipid compositions in particulate and in compact forms with superior bioavailabiIity, suitable for oral and other applications.
Background to the invention Problem drugs A major problem in delivering biologically active compounds to humans or animals concern poor absorption which may be due to:
(i) low solubility in aqueous media; and (ii) poor membrane P~'eability.
These adversely affect bioavailabiIity and reduce efficacy. The problem applies in particular to Iipophilic compounds and presents a difficult challenge, particularly to the pharmaceutical industry from both technical and commercial perspectives.
Commercially, the inability to improve bioavailability may be costly if the time to market approval is either delayed significantly or prevented. Indeed, numerous compounds that possess promising pharmacological activity are abandoned in the late stages of development because of poor and erratic bioavailability. In some Wp 00/33817 instances it may be possible to improve bioavailability by forming a derivative that is more hydrophilic without unacceptable changes in pharmacokinetics_ 1t is di~cult to find a carrier system that improves the bioavailability of lipophilic compounds, which is efficient and non-toxic for oral administration and can be manufactured in conventional solid dosage forms_ Ethanol and ethoxylated surfactants are widely employed in liquid compositions although there are serious limitations in their use. Another approach is to have the active material in a colloidal form or as a co-precipitate with the aim of improving dissolution characteristics_ However, this may not completely solve the problem because the low membrane permeability may still defiy efforts to improve bioavailability_ Problems of poor bioavailability are not limited to hydrophobic compounds. Some hydrophilic compounds with large molecular weights may give similar problerns_ Examples of hydrophilic compounds which are poorly absorbed include peptides e.g- insulin, peptidomimetic compounds, ant'bodies and genetic material e_g- oligosense nucleotides, etc. Poor bioavailabity in these compounds may be due to degradation in the upper GI tract and low membrane permeability rather than low solubility_ Carrier systems are designed to improve delivery and maximise ~onnance of active compounds_ The system m~ be compatible with biological P
systems and able to deliver the active compound in, a controlled manner. Above ~1~ ~e ~mponents used must be non-toxic and conform to specifications that give reproducible performance. Although oral administration is the preferred route of medication, compounds are sometimes delivered via alternative routes e.g.
i~~atyon, parenterally and transdermally. These routes can, however, create problems and are generally only considered when GI absorption is inadequate or cannot be controlled sufficiently. An efficient oral delivery system may provide 3o the key to unlocking the clinical potential of problem compounds in drug discovery prunes. In this specification, delivery also includes absorption pCT/G 899/04070 across the buccal and other mucosa. By improving the bioavailability or controlling the release of potent drugs, toxicity may also be reduced because of the smaller doses that need to be given. For compounds that are expensive or available only in small quantities, it is an important consideration_ The importance of delivery systems is widely recognised and the quest to improve and control bioavailability of problem drugs is one of the most active pursuits in pharmaceutical research.
Lipids as carriers for drugs to The benefits of using diacyl lipids, e_g_ phospholipids as carriers for drugs and other biologically active materials are well known. Phosphoiipids are the major component of Iiposomes, microscopic vesicles for carrying biologically active compounds. The production of liposomes is discussed inter alia m EP-A-0158441.
More recently it has been proposed to use as carriers anhydrous systems based on monoacyl lipids or on mixtures of monoacyl and diacyl lipids. WO
98158629 discloses a carrier system that comprises one or more monoacyl lipids or other related micelle-forming amphipaths, optionally in admixture with one ar more bilayer forming diacyl Iipids_ The system is when prepared normally in the form of an anhydrous or near anhydrous solid, waxy solid or liquid and -is contacted with aqueous fluid only in use or just prior to use. The effect of contact with aqueous fluid is that the carver system is converted into drug-associated lipid particles that, depending on the ratios of diacyI and monoacyl lipids, may be in the form of liposomes, micelles or mixed micelles. At this stage, a: lipophilic drug incorporated into the original carrier system may be present in a molecular form intercalated between the lipids making up ~ the lipid aggregates (Iiposomes or mixed micelles) or may be held in the form of a totally micellar Iipid-drug 3o complex. The monoacyl components both promote solubilization of a biologically active compound in a mixture of monoacyl and diacyl lipids and aid dispersion PCTlGB99/04070 WO p0I33817 into small aggregates on contact with aqueous fluid. Where the per comprises a p~~ly e~ytne-digested diacyl lipid, bile salts and other emulsifiers are noI
required for release of the compound from the gastro-intestinal tract as the compound is largely in molecular dispersion tn the partly digested lipid mixture.
However, as a bonus, dispersion into lipid aggregates may be further improved in the presence of emulsifiers such as bile salts particularly at 37°C_ p problem with 'Which this invention is concerned is that lipids are enerally not suitable for processing into solid forms under ambient conditions g exce t when used in small amounts. This is one reason that lipids, particularly to P
phospholipids, are not used more widely as carvers in effecrive amounts Summary of the invention An object of the present invention is to provide an improved carrier for o ~lic ~d particularly for hydrophobic compounds that has pharmaceutical hydr p and industrial applications.
It is a further aim of the invention to provide a carver composition that has -or bioavailability and is versatile, safe, efficient and cost effective to Per' manufacture.
It is a further object of the invention to modify lipid components that are soft or waxy sub~anc~ at ambient temperature, so that they can become hard (i_e.
'able or crushable) and can be c°nv~~ into free flowing powders that may be fn filled into hard gelatine capsules or the like, or may be compacted into solid forms f e.g.tablets.
It is a further object of the invention to provide an extended range of lipid materials that may be converted into hard comminutable compositions_ The invention provides compositions in non-liquid form that are easy to prepare, and that may be solid compacts or may be particulate. Most preferably they are based on monoacyl and diacyl membrane lipids on their own or in admixture or a combination of membrane lipids with other single chain 5 amphiphilic lipids. At least one solid hydrophilic substance, most preferably a polymer, is typically included in the composition.
At least one biologically active compound may be present in the lipid polymer associate. The active compound may be added to the solution or suspension of lipid and polymer before removal of solvent or it may be blended in with the lipid polymer associates after drying- In this case, the active compound may associate with the lipid polymer on hydration. Alternatively, the composition may be a mixture of e_g. two or more lipid polymei associates of different active compounds. Incompatible substances or compounds that work better when used in combination can be kept apart in separate lipid polymer associates_ Separation of active compounds in this manner within the same dosage form would not be possible in aqueous solutions_ The lipid polymer associates have the potential to swell in water or other aqueous media to form mscous intermediate compositions, which may or may not be bilayered_ Hydration may take place in situ e_g_ from powders or granules inside a hard capsule or from a tablet in the GI tract and other mucosal surfaces_ Depending on the proportions of monoacyl and diacyl lipid, polymer and other components present in the composition, the hydrated structure may further disperse in water and other aqueous media and reassemble into micelles, vesicles or mixtures of small lipid aggregates. Preference for the types) of small lipid aggregate formed depends on the properties of the biologically active compound and other requirements. Furthermore, release of a biologically active compound may take place from either the hydrated bulk structure or from the suspension of small lipid aggregates_ WO 00!33817 As far as the applicants are aware there has been no prior disclosure on ho holipids generally, particularly in the form of enzyme modified leclthm p sp containing hydrolysed phospholipids with GRAS status to form solid lipid polymer associates and optionally with biologically active compounds, to improve oral s bioavailability.
In this specification:
lipid refers to amphiphilic molecules bash on, or containing, either one or two hydrocarbon chains and covers mixtures in addition to single compounds.
Active Compounds are biologically active substances that have a physiological or pharmacological effect in a living organism.
associates are complexed structures formed between the lipid and 1 s L~p~d _ idly One or more hydrophilic polymers and optionally one or more active tYP
ounds. The active compound may be m molecular association or suspension comp i id- lymer associate. Alternatively, it may simply be mixed with the lipid in a 1 p P°
1 er associate. Lipid-polymer associates may be particulate with mean P° ~
tens ically between about O.OSmm to Smm or they may be solid diame tYP
impacts.
Small lipid aggl'egates are polYmolecular structures that may be foamed when the lipid polymer associates come into contact with an appropnate aqueous medium. These structures may be vesicular, non-vesicular, micelles, reverse micelles, mixed micelles, or mixtures thereof Description of preferred embodiments The present inv~~on provides for compositions in compact and/or m iculate forms, compnsmg at least one micelle forming single chain P~
hi athic lipid and/or at least one bilayer forming double chain arnpluPath~c amp P

Qcr~cs99ioao~o wo oor~3s1 ~
~i id and typically at least one polymeric material, optionally associated with an P
active compo~d_ Particulate compositions particulate compositions according to the invention may take the form of articles or granules. Although particle size is not a limitation, the mean particle P
diameter of the solid lipid polymer associates is preferably between about 50 prn to 5000 pin.
to Powder compositions may be obtained by milling or micronising using conventional equipment. Alternatively, the lipid polymer ~sociates may be obtained as free flowing powders afrer spray drying and other suitable techniques remove solvent. Powder compositions are suitable for filling into hard capsules to used as such. Fine free-flowing powders are towards the smaller end of the size or a 'ven above and typically have mean particle diameters between 50 lCm and rang gi 00 , referably between 100 pin and 1000 Eun, depending on the fill weight ~ P
of the capsule.
Granular lipid polymer associates may be between lmm to Smm m eter. The gr~ules may be obtained by comrninuting dried lipid polymer ~e diam b ~In acting powdered material into slugs and breaking them into granules_ or y P
ules may be used as such in various dosage forms or they may be further Th ?
compressed into tablets.
a Tablets Powders and granules may be compressed into tablets, lozenges, troches, buccal or mucosal tablets, pessaries, etc. Direct compression aids e.g.
lactose, 'croc stalline cellulose, dicalcium phosphate, etc. may be used if required.
In 3o ml er cases, sm~l qu~fities of active compo~ds may be mixed directly with the oth li id polymer associates for compression into tablets. ~ By using 2npropnate P

pCT/G B99/040~0 polymers and forming suitable associates, the invention enables waxy lipid materials to be compressed into tablets with good compression characteristics and properties e_g. uniformity of weight, hardness etc. The disintegration characteristics and dissolution profile depend largely on the type of lipid and polymer used to form the associates_ Thus the tablets may either disintegrate rapidly or more preferably remain substantially intact in aqueous fluid, thereby allowing controlled delivery of active compounds in the gastro-intestinal tract and other sites. Lipid polymer tablets which have become hydrated e_g_ by contact with saliva have good retention properties on mucosal surfaces and are 1 o particularly suited for mucosal e.g. sublingual and buccal delivery. They may be retained on mucosal surfaces for extended periods i.e. up to 12 hours or more de ending on the type of lipid, polymer and lipid/polymer ratios. Other P
appropriate excipients that may be used are preservatives, flavourings, effervescent agents, glidants, lubricants, binding agents, disintegrating agents, flow aids, colorants, antioxidants, etc. The Lipid polymer associates rnay be used e.g_ in pharmaceutical, dietetic, food, toiletry, cosmetic, veterinary, aquaculture, horticulture and other industrial applications, or where there is need to improve the solubility of poorly water soluble compounds ~~or enhance of control absorption of both water and oil soluble substances_ Lipid The lipids or other amP~Pa~c materials that may be made hard by mixture with a polymer according to the invention may have a single hydrocarbon chain, may have two hydrocarbon chains or may, as is preferred, be a mixture of a single-chain and two-chain materials. Preferred lipids are membrane diacyl lipids and their monoacyl derivatives but the definition also includes the mono- and di-esters and ethers of sugars and polyols, fatty acid esters and other fatty acid derivatives. These can hydrate and swell on contact with water to form lamellar or bilayered stacks. Generally, in excess watez, above the critical micelle concentration (CMC) monoacyl lipids form micelles, whilst diacyl lipids above the phase t~tion temperature (Tc) tend to arrange as bilayered vesicles or p['I'~G 899/04070 reverse . micelles. Preferred lipids are amphipatluc membrane lipids e-g-phospholipids, glycolipids, ceramides, g~gliosides and cerebrosides.
_ Preferred compositions are compacts or powders comprising at least one monoacyl membrane lipid component. However, monaacyl and diacyl membrane s ii ids may also be used on their own. Most preferred compositions comprise F
mixtures of at least one monoacyl and at least one diacyl phospholipid. One or ore charged monoacyl or diacyl lipids may be included to improve the m association, hardness and hy~ation properties of the lipid-polymer associates.
The com ositions may comprise other single chain amphiphilic lipids in significant P
amounts in addition to phospholipids_ Although it is preferred to have the active m and in molecular association with the lipid polymer, the active compound co po also be in solid suspension. As a general rule, it is preferred to have lipophilic may unds in solid molecular solution, whereas hydrophilic compound may be compo s ension. Strongly hydrophobic compounds may require larger amounts of ~5 in su p a sin le chain component or single chain component on its own for complete th g molecular solution.
Sin le chain materials preferably comprise a monoacyl derivative of a g tral or charged phospholipid, but it can also be a monoacyl derivatives) of a 20 neu 1 colipid and sphingolipid. The lipids may be derived from natural plant, or gY
al or microbiological sources, synthesised or P~lally synt3~esis~' including anim th leneglycol (PEG) derived monoacyl phospholipids, e_g. pegalated PolYe Y
ac 1 hosphatidyl ethanolamme Examples of charged monoacyl mono y P
holi ids are the monoacyl derivatives of phosphatidic acid (PA)~
2s phosp p hatitd 1 inositol (Pl), phosphatidylserine (PS) and phosphatidylglycerol phosp Y
G . Examples of neutral monoacyl phospholipids are the monoacyl derivatives (P ) hos hatidylcholine (PC), phosphatidylethanolamine (PE) and sphmgomyelin.
of p P
ltemative amphiphilic single chain lipids e.g. fatty acid and alcohol, propylene A
col lycerol, or sugar mono ester ~d their denvatives may also be used alone 3o glY ~ g referably in combination. The hydrocarbon chain can either be unsaturated or or p saturated : nd can have between 10 to 24, preferably 14 to 18 carbon atoms_ The double chain lipids) is preferably a phospholipid but may also be mixtures with other amPluPlulic diacyl lipids whose monoacyl derivatives have been mentioned above. Charged membrane lipids may also be used on their own or included in the mixture- The aryl chains can either be unsaturated or saturated and can have between 10 to 24, preferably 14 to 18 carbon atoms. Other membrane lipids, such as glycolipids, cezamides, gangliosides and cerebrosides can be used in place of, or in partial replacement of phospholipids.
Although the Lipid composition may comprise entirely of at least one or ore sin le or double chain component on their own, preferably the weight ratio 1o m g of single to double chain lipid in the mixture could be from 1.99 to 99.1, referably between 1:25 and 25:1 and most preferably 1:10 and 10:1. It is also P
ssible that lecithin containing high amounts of naturally occurring monoacyl po id coin onents within the aforementioned range may be used i_e. above about 3 lip P
o w/w referably about 5 %w~w. Deoiled lecithin is an example of such a lipid 1 S /o ~ P
d_ -1-his may be obtained from either egg or soya bean. Mixtures of lecithin blen a acid mono- and diesters and ethers of sugar, alcohol, polyglycerol and with f tty their derivatives may also be used_ In the case of phospbolipids, instead of mixing pie fractions of the two 'ds to obtain the targ~ ratios, partially enzyme hydrolysed mixtures of Lecithin lips that have the require propo~ons of the monoacyl to diacyl Lipid components are articularly pref~T~- These phospholipid mixtures, which are known as enzyme P
ih~ lecithins are freely permitted in foods without restrictions and should mod resent no problems for oral use. Wherever possible hydrolysed lecithin 2s bus P
,n from 5 to 9S preferably 60 to 80 mole percent of monoacyl contai g holi ids obtained by enzyme hydrolysis with phospholipase A2 is preferred.
phosp p a lecithin should be substantially pure and substantially free from non-polar Preferably the lecithin is GMO free or does not contain detectable levels of lipids genetically modified components.

PC t/GB99/04070 II
Lip;d~Active ratios The uantity of lipid employed to form the associate depends on a number q -derations. These include the amount of active compound present and its of cons emical characteristics. The type and the charge of the lipid or lipid physicoch -Xture are also factors to be considered. Where the invention is required to carry ounds substantially in molecular association, higher amounts of lipid active comp a re uired to form the as~~ates. Lipid: active compound ratios of 99:1 or may b q more may be employed in the case of extremely potent compounds or even 1 h drophobic problem drugs- In most cases, lipid: active ratios between to strong y Y
to 1:40 would be su~cient, depending on the type of lipid and the charge.
40:1 id: active ratios between 20:1 to 1:20 may be quite sufficient to (i) Usually lip solubilise lipophilic compounds or (ii) subsequently improve the substantially bioavailibility of both lipophilic and hydrophilic compounds.
IS
1 less lipid is required to solubilise lipophilc compounds if General y, ~ons of monoacyl component are Pr~en~ reducing the total higher proporti li id in the composition. This is also the case where the active amount of p d is h drophilic and the lipid polymer composition is used mainly to compoun Y
lion and improve bioavailability at the site of absorption. Where the 2o control hydra m o~d is dispersed as discrete particles in the lipid polymer active co p sitions, they should be less than lpm, preferably below 250nm. m~
compo diameter.
25 Polymer a impositions typically contain one or more polymer dispersible or Th of water or an organic solvent. Water miscible poly solvents e.g. C2 -soluble in h hols esters or ketones are preferred, although solvents that are non water C6 alco , also be used to disperse or dissolve the polymer. The amount of 30 miscible may to ed may lie between 5%w/w to 90%w~w or more, preferably polymer emp Y

10%Ww to 75%w/w depending on the required hardness and ~ hydration characteristics of the lipid polymer associate_ ~e polymer may typically comprise less than 50% by weight of the m sition_ However, this is not a strict requirement. The polymers) is normally co po ed as a solution in an organic solvent or hydrophilic medium and the solid add associate is formed after solvent removal_ In cases where the polymer is lipid ater soluble, the solvent may be water. The definition of hydrophilic medium w a also extend to sugars in some cases. Indeed, sugars can be regarded as a my h dro hilic medium- 'This may be the reason why combinations of to solid' y P
ers and some sugars are Particularly effective in hardening lipid. Mannitol, polym I and xylitol and combinations thereof are suitable examples for use with Iactito ers in the solid lipid compositions. Higher amounts of polymer produce polym sitions that are pier to tam into powders and granules and for subsequent compo lion into tablets or the like. The compositions particularly in the form of a ~mpac -d com act, also tend to take longer to hydrate and swell and are therefore more soh p suitable for longer retention on mucosa e_g_ buccal mucosa_ ater insoluble polymers may be dissolved or hydrated In an °rg~'c W
ent e. . ethanol, together with the lipid and the active compound to form a 2o sole g eous solution or dispersion ~n the fast instance. Where water-soluble homogen ers are used, they are dissolvedlhydrated separately in water before adding polym a or anic lipid solution. Removal of the. hydrophilic medium results in an to th g -drous or nearly anhydrous solid Iip~d polymer association structure anhy ~entl hard to be micronised or turned into granule suitable for compaction, 25 su~ci y Alternatively, during removal of the hydrophilic medium, the e.g. tabl -on may be spheronised or pelletised. Removal of the hydrophilic composlts ~um may be c~~ out by any suitable method, including vacuum drying med~
d in , lyophilisation or a combination of more than one method_ Polymers spray rY g ids with a low melting point e.g. below about 30°C and natural 3o allow lip phospholipids with low ph~e transition temperatures that are unsa PCT/GB99/040?0 Nrp 0013381?

teristically soft "'razes at room temperature to be more easily handled for charac in into solid and particulate forms. They also allow larger amounts of process g holi ids to be used. Use of time dependent polymers ~~ different swelling phosp P
ro erties may modify hydration of the solid lipid associates in aqueous P P
nment and offer a method to control and prolong the release of active enviro unds in the G3 tract. Protection against hydrolysis and breakdown of the compo d active compound in a low pH aqueous environment e_g. stomach, is lipid an Bible if the polymer used is insoluble in acid medium. The lipid polymer pos ~ates may hydrate and swell when the pH is raised to release the active associ ound. In this way, drugs may be targeted to the lower regions of the G1 tract.
to comp eferred polymers for hardening lipid are the natural gums and Pr -I-he may also be synthetic polymers e.g. methacrylic polymers and derivatives. Y
vinyl polymers and copolymers. Gelatine or partially copolymers, carboxy s~ elatine may also be used. Most preferred polymers are the celluloses hydroly g methyl cellulose, ethyl cellulose and combinations of cellulose ~~
e.g. carboxy r me~acrylic polymers- Sodium alginate may also be employed on its alginates o ches and modified starches e.g. maize starch, phosphated starch, own. Star -raised starch, hydroxypropylated starch and starch sodium pregelah lose content are particularly octenylsuccinate, etc, and those with a high amY
Monoacyl phospholipids complex with amylose and form lipid associates suitable.
der and have good tolerability combined ~~ g°°d physical and that are har 1 stability. They may be preferred for making hP~d polymer associates to che;tntca give improved bioavailabilty.
Char ed p°lYmers significantly increase lipid hardness_ Some of the best g - ~d~ing polymers have negatively charged carboxyl groups (such as lipid h 1 mate and Eudragit L100 - methacrylic acid copolymer) or negatively sodium a ~
ed sul hate ester groups (such as carrageenan). Charged molecules are charg P
more soluble in aqueous media, rather than organic solutions, and ~s is 3o generally are more water-soluble polymers that can harder' the lipid than ethanol-why there .

oluble olymers. Generally, suitable lipid-hardening polymers that are ethanol-s P
oluble are also soluble in aqueous media as Well, at appropriate pH.
Preferably, s of mers should be dissolved or at least parUally dispersed in a solvent before P y being dried with the lipid to increase hardness. Heat may be used.
Table I summarises the charge found on a number of common pharmaceutical polymers.
le 1. Charge ch~'acteristics of a number of natural polysaccharide and Tab to synthetic polymers commonly used in the pharmaceutical industry.
Charge Ionic Group Polymer _ -~_x:...., ~,ft,oxvmcthylccllulosc ICarmdlosc sodium) Acidic or amonn Acvd~c- or a A1 inic acid -_ _-Acidic or anionic Carboxyl Sodium al inatr Acidic or anionic Sut atc Ett _cr Modificd srarchcs Acidic or anionic c Ea~

A gay-- ~ Acidic or amionic ~rbx l Acidic or anionic CarDox !

G=m~ (Acacia) -" -Acidic or anionic Carboxyl ~ =nt- Acidic or anionic Carbox Gum x~~~
Acidic or anionic Carbox Pcctin - -hvlearc (Carbomal ~-----Acidic or anrontc Carbox w-w--' I

~x olvmct -/ Malcic Acid Co olvma Acidic or anionic Carbox Mdh 1 Vinvl Ethrs Am I1. Ionic Salt McthacTVlic Acid Co I c Amino o r ym Basic or canom Amino Anutwntio Mc~ latc Co ic 1 cr i = c latc $ on I
Basic or cat i i as c on Ncutral or non Chitosan .-- Npnrai or nonionic i I Starch Neutral or nonionic I

f1 droxvcth lccllulosc 1'l~l or nonionic I _ H ~x Icdlulosc th Iccllulosc h1~ I Neutral or nonionic I

I-lvdrox ro Imc ricvtral or nonionic /

Girn -Gum (C~tonia /
Ncutral or nonionic .

Carob bcan Ncutral or nonionic I

Pol (vin 1 alcohol -) (Povidonc) c I

Pol hn 1 ~lidonc c~lornootonm .___..r.,....tctlMacroFolsl..,_.___..,..v N

block of ers modify the physical characteristics of soft or wa~:y lipid Z 5 P yn' ces. -I-hey also affect the formation of intermediate structures on hydration substan con~e~ion of these structures to small lipid aggregates in water or other and us medium_ Biologically active compounds are found to have extremely aqueo association in the anhydrous solid forms, the hydrated structures and where high ro riate, the resultant aqueous dispersions of small lipid aggregates.
Polymers 2o aPP P
im rove the association between the lipid and the active compound and t,rther P

WO 00/3381'1 ete association between the lipid and the biologically active almost cornpl be ssible. They may improve chemical and Physical stability compound may P°
tect the lipid from oxidative and hydrolytic decomposition_ Polymers and pro id compositions that are tolerant to relatively large amounts of provide solid lip sorbed or deliberately added water without significant deterioration or 5 residual, ad h sical properb~ such a_s flowpropert~es, friability and softness.
changes in 1 P y -d 1 er associates stored in glass containers remain free flowing Powdered hp~ P° ~
after storage for 3 monk at 40°C and ~5%~-f the natural polysaccharide polymers, starches and their Most o ulose olymers and gelatines are pharmaceutically acceptable for derivatives, cell P
~d topical admimstration_ From their widespread use in food, they oral, mucosal, erect to represent a hazard to health. Table 2 summarises the are not consid teristics and lipid hardening proPert'es of some of physical charac tical olymers. It must be clearly understood that this is not an 15 pharmaceu P
d other hydrophilic polymers not included in this hst may also be exhaustive list an ers ma be used in combination and any suitable method of mixing suitable. Polym y ova can be employed to produce solid lipid polymer compositions and solvent rein on a commercial scale.

pCT/G B99IOd070 r form ing lipidmer f poly solids o polymer ble 2 Example formulatiotu_ of Polymers that may be suitable used in Iipid ers .T
l a .
h ym e armaceutical po p Characteristics of som desia= pe~sw pd H F~
Lipid Hardcwia~

r CYar~C SahKwt Sshtbairy~ ~~tiscd Polymc p l ou Poi bk in warn Very gr Ihs good- p solid Cafioay lucnsc monomers tbvkdlulosc ~ hard C~'xYl rbxY'e Acidic nr anionic and FTttP
Insnlubk in ctlunnl drv n od solidJ-mluronic V acid _ Sodium ca nionc Sobtbk in waterery g and llasc sndiuml rd and wunnuron:c drv xid h narnmcrs CarnK Acidic or a a 1 Itsolubk in dhanol ~ solid CarbOI
al iNtc V 1 - Y
PuP

m $odlu g Swellabk in water t:ry i OnIC 6 d C

d ACIdIC OT aN ur n (~K~ Very Sulpluted ~ solid agarox and a fatpcct s n r"
l M(t Acidic or anionic lord F
1 Soluble in_hot waterand P
ble m ethanol dry polymers l wittl orboxY
ltruroruc xid nwtlomas oC
!

APr u t Inso e . g a tin Very Sulphatr~
B~ slid galactse and ~

Acidic M anionic hod and anhvdro Soluble in lid waterdrv bc>se bk in raLanol n'r'm _ on Elucuromc xid rou l C~rnl'uan lmolu Good. p sd~ g hard Carboxy Acidic or anionic and drv monomers Soluble m water ~uP
ble in ethanol on l 1?~ronic box C

is Ancia) Gum anb ( u good. y Inso solid 6 Vcrv ar t' Acidic or anionic _ xid Soluble in wakr hard moome ble is cthannl and oP
l drv n Flueronic xid l h Gum znf~h u V cry oay inso god El solid Car Acidic or anionic hard mortnrncts Soluble in wattt and Carboxy lrtwlubk in ctharol d group Plxwronic Gum xanthan Soluble in watcT Vcry ~
6od-solidm"m'2 i Acidic or anionic hard Carboxyl insoluble in dhanol and AoWs d V erY synthetic 6d-solid n Pect Acidic or anionic hard 1 (Vrbter) Soluble in water and Carboxyl Soluble in ctharol drv goups lid on synthetic ~ Y~ ~ n Very x 1 ykne 6''d so I Makic Acid Acidic or anionic hard 1 Soluble in war and CaTbxYl Soluble in ethanol d Poufs lid on syrthctic 1 a9"es F~eelknt.PIY~
~ (~n~ S) r anionic So so i V in 1 Ether i txisPy Mcthy Y ~
bard y d p .
lie Acid Copolymerc o drv Acid > H7 ) Soluble in cthatt) Very Ammo.ebloride ater god- sah solid io Medtaerylate Ionic Sale Pcnrlobk hard CPIY~ m w ad drv Amino n Soluble in dha~l Very g7oops Fod on solid sYothdc Amnio Basic or cationic (~'n Rt-~RSI Soluble in aqttN'ts hard pIYt'~
and dry Basic Polyrndhaaylatcble in ethanol At~~
(Eudngit E) l ~
S on benhtiscd u Very o 6oL ra slid Hasie or euionic Curd glucose a and morw>r>e ediak ~ PH dry Chirt>s>n m Insoluble in dlunnl /

Swellabk in Mt water1"1~tc i c Neutnl or nonion Mod Soluble in water Starch Neutral or ttonbtttc insoluble in dhanol H~xycthykc11u1oscSoluble in water Modcraa i c Neutral or nonion r Soluble in dlurol HydraYPrPYledlubx ;wwata M~tc Soltbk i Ilulase c N~1 or ranion ate /
Inwlubk in dhanol d H~mz~y Sohtbk m whet er Mo IH mcllosd Ncutnl or nonionic Insohbk in ehaclol t Gum sitar Soluble in water Moderate i (Cetatonia) c G Nc>nl or ronion te htsohtbk in ctharlold um Soluble in water Mo ~ bdn i era c Neuual or nonion NitroEcn atom Insofabk in dhartol oC cyclic amide may Poly(vinyf alooltI)Soluble in water Gd- form wcalc electrostatic i intcrxtioru c IuSonc) (Povidonc) Nattnl r nonion Soluble in ahanol Poly(tr;rtYli'Yrr as found that the aPPe~nce of the composition was not sigrufi~tly It w d b olymer con~ntration_ Using the present processing and- drying influenrx Y P
a ~n~~ mount of about 10% by weight of at least one polymer, methods, a total weight of the solid composition, w~ required to substantially based on th a soft lipid. High shear mixing, for example would allows the use of less harden th 've a homogen~uS composition prior to water removal. Hot air or water to ~
assisted drying methods are also efficient in reducing the processing time vacuum pC'f/G 899/04070 and reducing residual water content to give stable and harder solid lipid com ositions. However higher amounts of residual water up to about 30% wow P
may be tolerated without adversely affecting hardness and other physical characteristics-'Thus it may not be necessary to remove water entirely from the com sitions. Any suitable method for drying and removal of solvent may be P°
em Toyed, including but not limited to e.g. fluidised bed drying, spray drying, P
freeze drying, supercritical fluid extraction, or a combination thereof.
Biolosically active compound to The compositions may finer comprise a biologically active compound which has lipophihc an~or hydrophilic properties- Preferably, it is in solution in ~e composition but it may also be in suspension_ ~~pl~ o f biologically active Iipophilic compounds include hydrophobic neutral cyclic peptides e.g. cyclosponn A. Taxol, tacrolimus or a macrolide e.g- a raP~'yc'~ ~d derivatives thereof are also suitable examples.
xam les of hydrophilic biologically acrive compounds include insulin, calcitonin E P
d he arin_ Another unrelated group of compo~~ which may be used with p vanta a are antioxidants, e.g. ubiquinone, tocopherols, carotenoids, and 2o ad g ioflavonoids. Other therapeutic classes of compound, may also be canned in the b vention. The type ~d the concentration of active compound in the composition m depend on the aPPI'~non and are not a limiting feature of the invention.
The invention will now described in the following examples, which illustrate inter alia the effect of varying the lipid and polymers on the formation ~d ro roes of the solid lipid associates, and the use of different lipid and P pe 1 ~ ~,i~ ~d without biologi~llY active compounds to obtain solid P ym articulate lipid associates that may be used as such, as powders or granules, filled P
into hard capsules or the like, or compacted mto e.g. tablets or the like.
urthermore, the lipid polymer associates have the potential to hydrate in situ, in F

water or other hydrophilic media e_g. intestinal fluids, to form drug carryng small lipid aggregates with high entrapment and good bioavailability.
Preparation of solid polymer lipid Example 1 A solid associate containing cyA, Phospholipid and a methacrylic acid 1 er was produced using a two-stage process_ The first stage involved copo yin solvin 5 parts of lipid, 1 part of drug and 2 Parts of ~e P°IYm~'n a minimal to dis g uanti of ethanol- The lipid blend used in this formulation had a PC: MAPC
q tY
ei ht ratio of approximately 33:66. The components were ultrasonicated at 50°C
w g dl ~ o tically clear ethanolic solution was obtained. 'tee second stage involved un p r~o~ng ~e ethanol by vacuum drying at 50°C for approximately 6 hours to duce a solid lipid polymer ~ociate_ The sample was weighed to a constant is pro i ht to ensure the complete removal of solvent from the associate. In this we g am le the cyA w~ in complete molecular dispersion_ The resulting associate ex p as a friable light yellow solid, which could be comminuted into Iipid/polymer w ules about 1-2 mm in diameter. This powder was blended with 25% by weight gran .
f rnicrocrystalline cellulose and the resultant composition was compr~ed into tablets that did not disintegrate in simulated gastnc fluid_ Example 2 A solid associate containing cyclosporin, phospholipid and povidone was roduced using the meth°d described in Example 1. The required amounts of cyA
P
1 ~ by weight), lipid (5 parts bY weight) and povidone (6 parts by weight) were ( P
wei hed into a drying vessel. The PC=MAPC weight ratio of this lipid was a roximately 33:66_ The solid components were dissolved in a minimal amount PP

pC'fIG B99I04070 of ethanol by ultrasonication at 50°C_ The optically clear yellow solution w~
cuum dried to remove ethanol. The resultant associate was a firm glass-hke va id that could be comminuted and that was suitable for filling into hard gelatine sol capsules- The cyA was in molecular solution in the lipid_ Example 3 A rufedipine ~phospholipid polymer associate was produced by dissolving b weight of nifedipine and 5 parts by weight of lipid (PC: MAPC weight lp~ y _ of 33:66) in a minimal amount of dichloromethane containing 2 parts by ratio i t of a methacrylic copolymer (Eudragit L ( 00) at room temperature- The we gh tart solution was subjected to vacuum drying until no dichloromethane could resul detected. The resultant yellow solid associate was kept in the dark prior to be in deionised water_ A dispersion was produced by adding 0-2 g of the hydrating (ex hydrated to form a solid lipid complex to 10 ml of deionised water_ The comp dis ersion, where the nifedipine was substantially in solution and P~ially viscous P
in suspension.
Example 4 An associate containing gnseofulvin, lipid (PC: MAPC weight ratio 33.66) era lic acid copolymer was Produced by suspending the gnseofi'l~ in and m ~y olic solution of polymer and Iipid_ The gnseofulvin: lipid: polymer weight an ethan ~o was 10:52.5_ The lipid: drug suspension was vacuum dried for 6 hours at rata to remove the ethanol. The resultant associate was an off white flowable wder that may be compressed into tablets or filled into hard gelatine capsules.
po Example 5 A Ii id associate containing lipid (PC: MAPC weight ratio 33.66). cyA
P
a Iic acid copolymer at a ratio of 5:1:0.67 was prepared following the ;p meth cry ethod described in example 1. A hard, waxy solid was obtained that could be m ken into granules- The powdered lipid associate remained in suspension in bro er below pH 6 and dissolved above pH 6. The cyA remained in molecular wat solution.

The methods used for forming the lipid associates described in examples 1 en, loy simple vacuum drying at elevated temperature, followed by a P
omminution process to break up the Enable lipid complex into granules- Any c ro riate method would be suitable for scale up. These include spray drying, app p to lyophilisation, supercn~cal extraction and spray congealing-Preparative method used in the following Examples The solid lipid composirions prepped with active material and water-is ble lymers, were made using the following general method. Unless solu po ise stated Sg of the dried lipid polymer composition was prepared m each otherw e. Much larger ~o~~ may be prepared by the use of appropriate equipment cas The li id and active (if present) were dissolved in ethanol. The polymer was P
ted in water which may be heated to about 50°C to obtain a viscous solution.
2o hydra 1 er solution was welded into a glass far and the lipid/ethanollactive The po. yin ion was added. 'The truxture was stliTed thoroughly until a homogenous gel dispers .I-he el was vacuum dried at 50°C10.1mBar for ~24hours to remove all formed g the ethanol and water.
25 L,tpid type Examples 6 - 7 Solid lipid polymer compositions shown below were prepared follov~nng thod described above using two different types of phospholipid which the me canal differed in their phosphatidylcholine (PC) and monoacyl signifi Y

hosphatidylcholine (MAPC) contents and sodium alginate. It was found that the P
appearance of the solids was influenced to some extent by the type of lipid used in the formulation_ For example VP 145 contains about 50% by weight of PC and S%
by weight MAPC, remainder glycolipid and other polar lipids, generally produced darker coloured and slightly firmer solids than equivalent formulations prepared with the lipid (VP 200) containing about 60% by weight MAPC and 40% PC. It is to be understood that in place of the VP145 and VP200 lipid used in the following examples, egg phospholipid containing 60% or more of PC may be used. Indeed I00% PC obtained either from egg, Soya bean or other natural or synthetic sources ip may also be used on its own. The hardness of the resulting lipid polymer associates may be adjusted by varying ~e mount and type of polymer used accordingly.
Appearancc Atter aryiag Dry Escipicatc Ex~,mplc No. Sample VPt4S/NystacicJManuBcII.BBGoldrn brown cnuhablc VPl4S lipid. (SO : 2S : 47.5) solid l ' to I mer tlow finc fiowablc Y

sodium a ~~~~~~~usclLBB c V~~ 1 51 wdcr .~ 25 : 47 ,te oolvmcr .
7 :
. ( 1$
The powder in example 6 was ground in a mortar and pestle to produce a free flowing powder. 3g of the resultant powder were stored in Sml glass vials at 40°C/75RH_ After 6 months of accelerated storage, the powder remained free-flowing. In place of VP 145 & VP200, egg phospholipid containing about 60% of 2o PC may be used_ Polymer type Examples 8 - 16 Several different polymers were used in examples 8-16 with VP145 lipid to establish the type of polymer that would be suitable for hardening the lipid. The solids were prepared using various concentrations of polymer, either in aqueous 3o media, in ethanol or as a dry powder according to Example 6- and 7. The lipid was WO 00I338~7 ersed in an equal amount of ethanol (wlw) before adding to the polymer. Tile dlsp experiments wed out are summans~ In the following table.
Appnrance After Drying Exampic Sample VP145 Golden r~
A
No polYn'~ Gotdrn slightly hard dry solid V P 145lAcacia Gum Arabic (70 : 30) -ighr Soldcn crispy hard solid VP14S/XanthanFld -l0 Gum Xanthan (70 : 30) Light golden VP14S/GclcarinGP379Ncrispy h~ solid 11 Cart'g''a" (70:30) VP14S/ GantrczS-97BFLigju goldrn crispy bard solid Methyl Vinyl Ether/Maleic(70 : 30) Acid Copolymer Goldrn slightly ~Y solid Polyvinyl Alcohol (70 : 301 Goldrnslightlywaxysotid 13 VP145/I'latrosol?SOGpharm Hydroxycrhylcellulosc (70 : 301 Golden slightly waxy solid l4 VP145/KlucdGFEP

HydroxyproPYlcellulosc (70 = 30) Golden y~low hard solid s5 VP14S/Blarrosc7LF( Ilakcs __._---Sodium Carboxymechyt~cllulosc (70:30) l6 a charge density on the polymer influenced the hardness of the lipid ociates. Gum arabic polymer, for example, consists of monomers of polymer ass inose, D-galactose, L-rhamanose and D-glucuronic acid, in the approximate to L-arab 3:3:1:1 _ Since only the glucuronic acid monomer is charged, the polymer ratio of w char a density and had only average lipid-hardening properties. Sodium has a to g the other hand, consists of D-mannuronic acid and L-guluronic acid alginate, on both of which are charged. ~ls polymer has a high charge density and monomers, od li id-hardening proP~ies. Furthermore, the use of combinations of j 5 had very go P
two or more polymers is not ruled out and may be preferred in some cases.
er d ing at 50°C/0. lmBar the majority of the ethanol and/or water had Aft rY
removed from the compositions to give a solid, crushable lipid polymer been sition at room temperature. The solid composition of Example 16 w~
20 compo usin a Culatti Mill wl~ a 1 mm screen to produce a free flowing powder.
milled g .
id lymer was compressed directly In a tablet machine to fomn compacts The Lip po -n a roximately 400 mg. In a separate tnal, the powdered lipid polymer weighs g PP
'tion was blended with three separate direct compression aids namely, compose lactose, micro crystalline cellulose and calcium diphosphate and compressed into tablets_ The ratio of lipid polymer associates to compression aid varied from.5% to ys% w/w. 'The tablets made were satisfactory.
The above exampi~ are placebos to illustrate the invention and do not contain biologically active compounds. However, it is confidently predicted that both li philic and hydrophilic compounds may be used in the examples.
Po icall , lipophilic compo~~ would be dissolved or dispersed in the ethanolic Typ Y
li id solution prior to combining it with the aqueous Polymer solution.
P
dro hilic compounds may be in aqueous solution with the polymer_ Lipid i 0 HY P
er associates with active compo~d in solid solution or dispersion are polym obtained on removal of the solvent.
Example 17 A li id polymer associate composition composing 20 parts of VP 145 Iipid P
d 15 arts of carboxyme~Yl celluose and 5 parts of mannitol was Prepared.
an P
The Ii id was dispersed in a small amount of ethanol (wlw) before adding to the P
a ueous olymer and sugar solution. The slurry was drced under vacuum as in the q P _ evious example- A ~d cue W~ °btamed, which was milled in a Culatti mill pr usin a lmm screen. The powder collected was free flowing and mostly below g average weight diameter.l part of Nystatin powder was uniformly blended 1 mm with 49 arts of the powdered lipid polymer associate. The resulting composition P
may be used as such or it may be tabletted.
Polymer Grade Examples 18-20 Solid lipid polymers were prepared v~nth ~' 145 lipid and Nystatin as the biolo -tally active compound in a ratio by weight of 20:1- The lipid and active in edient wee disperse in equal amounts of ethanol (w/w) and then added to an gr aqueous solution of a polymer (Manugel LBB or Keltonel LVCR). In principle, there was no upper limit to how much water could be added to the lipid-nystatin-polymer compositions before drying, although large amounts of water required alternative processing methods e.g. spray drying- In practice, a minimum amount S of water was necessary to produce a hydrated lipid polymer composition that was suitable for drying from slurry- The dried composition may be filled into hard gelatine capsules or the like or it may be tabletted_ pry Exeipie°ts APPcannce After Drying Example Sample I8 No polytt>Q ' POl4 ,/Nyststin Ycilow wmcy solid 19 47S% Sodium Alginate VPI45/Nystatin/trlanugdLBB Golden herd ccnsh~ble solid f50 : 2S : 47.5) 47 5 / Sodmm Algttate ~i';'S"''y"'""~eltoneLVCR Golden hard flakes 20 , (50 LS 47 5) Hardness Examples 21 - 24 -I-he amount of polymer in the formulations below was paned to see how this affected the 5na1 hardness of the solid. The solids were prepared using a 4%
or a 6% Keltone LVCR polymer solution and incorporated VP200 lipid and cyA
as active ingredient in a ratio of 5.1. The lipid and active ingredient were dispersed in an equal amount of ethanol (w/w) before being added to the aqueous polymer solution. The solid compositions from Examples 23 and 24 were articularly suitable for powdering and filling into hard gelatine capsules.
Each P
Sppmg capsule contained SOmg of cyA. Alternatively the granules could be compressed into tablets.

~ pPPcsranee \ftcr Dryios ---.-"" Eicipicuts Sample E:ample Yellow ~

VP2001CyA

No polymer 21 (8333 : 16.67) ----.
Yellow dry solid wnh a slight 10%. Sodium VP200ICyA/SodiumAlgmatcshine-~~ krnu Alginate (75: 15 : i0) Yellow hard crispy solid - an Sodium AlginateVP200/CyA/SoJiumAlginatebe cn>shed %

. (66 67 : I333 llow hard crispy 20 : 20) slid -dium Alginate VP200ICyA/5odiumAlginatcPale ye can be c~ to tlakcs 24 /. So (58.33 : 11.67 Extremely hard : 30) solid.

te VP200/CyA/Na inutablc to fine i Alg/XYlitol owdcr.

na (433 : l 1.7 Comrn 30/. Sodium : 30.0 : I
Alg S ) 15/. X litol Flow Properties Example 26 Componrnts Ratio w/w App~c aRcr dt71in8 VP200INaCHIC 50:70 Briulcycllowflakcs 20 of a Lipid complex containing X200 (50%) and NaCMC (50%) was t0 g in the usual manner. The dried lipid polymer associate was milled using produced micro hammer mill through four screens with diameters of-. 1 mm, I.5 a Culatti and 4 mm- After milling all four powders uniformly filled into HGCs mm, 2mm ~ve of the screen diameter. The resultant free flowing powders were sized irrespecti owders is is using Endecotts _sieves. The particle size distribution of the four p '~ a 1.~'he powder milled through the 1.5 mm screen was filled into provided i ~Figur.__-0 hard eiatin capsules using a Feton filler. The mass of powder ms>.de nine size g es was remarkably uniform. The mean capsule weight was 0312g With the capsul a narrow standard deviation of 0_008 g.
2o Stability of lipid Short-term stability studies were carried out to assay for degradation of the oth during manufacture and after storage of the lipid polymer solids. The lipid b of the lecithin components PC and MAPC were followed by HPLC
a stab>llty anal sis. During the manufacturing process the Iipid was subjected to high y tempera~re hydrolysing conditions for several hours which could easily have h drolysed the PC initially to MAPC.I However, it was found that the lipid was Y
stable both during manufacture and on storage of the lipid polymer solids S
Association of active ingredient in solid lipid polymer compositions Examples 27-30 The examples below were prepared according to the method used in the revious examples. The ass°~ation of the active material with the lipid was P
determined using analytical filtration. The assay for the active material was carried out by HPLC. The results indicate that near 100% association of the active material in the lipid polymer associates is possible even a$er up to 3 months 15 storage at elevated temperature.
A 40 g sample of the composition described in Example 27 was Produced and ground in a mortar and Pestle. Twenty 2g samples of this composition were ored in a 4m1 glass vial. After 6 months storage the samples were physically and st chemically stable. Under the conditions tested, after 6 months storage at 40°C/75%RH, the Powder had a moisture content of about 15%w/w and still rained free flowing.

pCTlG B99/04070 ~p~apow ~xsmple Compositiow Esciptents 27 Lipid/CyAlSodiumCTrIC VP805/CyNBI~n°sc7LF Initial--100°/.
(50_10:40) 1 month-971%(4°C).98.6%(25°C).
98.0°/. (40°C) 3 months - 98.8% (4°C). 985 % (25°C).
98.8% (40°C) 6 months- 98.0°/. (4°C). ~.8% (ZS° C)_ 91.6% (40°C) ZS !.i eid/CyA/Eudr~B~t VP805/CyA/Eudr~g1IL100 1 ~p~ ,~9,/
(4°C).971°.b125°C).
P
(50:10 40) 98.1% (40°C) 3 months- 98.9% (4°C). 993 % (~°C)~
985% (40°C) VP145ICyA/Ma"ug~LBB Inilizi-93_4%
Algin~tc 1 month- 101 4 % (40°C) LiP~Cyp/$odium (50:2.5 47.5) 6 weeks- 102.0 % (~°C)) 30 Lipid/Cy ~B~CY~t~ugclLBB iwitial-961°/.
p/Sodmm 1 month- 100.0°~ (~°C) 6 weeks- 99.7% (40°C) Algitmte ( '47.5) Activity of lipid polymer solids The activity of the drugs in the Lipid polymer solids was assessed usung a formulation. Nystatin was chosen because its activity could be assessed nystaiin sim le in vitro microbiological assays- The antifungal properties of nystatin using p li id solids were assessed using a cup-plate diffusion assay. The solids were to F
in a ueous media to form Lipid dispersions, which were compared to equal diluted, q trations of a commercially available nystatin suspension, NystarfJ (E. R.
concen uibb and Sons Ltd.). Tryptone-Soya agar plates were used that had been Sq Candida albicans NCPF 3179 to a final concentration of 106 inoculated with viable cells per ml. Solutions were incubated in 5.5 mm wells for 2 hours at room lS
erature, followed by 18 hours at 37°C. The zones of growth inhibition of the temp Candida albicans were measured and compared in Figure 2.

pCT/G B991040?0 WO 00/3381?

Examples 31- 33 In Examples 31 to 33, three different starches were incorporated with VP200 lipid to illustrate the use of these polymers for hardening the Lipid.
The olids were prepared using various concentrarions of polymer in aqueous media.
s n exmnple 31, the lipid was dispersed in water without ethanol, before being I
added to the polymer- In examples 32 and 33, the polymers were dispersed in hot water prior to the addition of VP 200 dissolved in ethanol. Examples 31 to 33 are base compositions of solid lipid polymer. The biologically active compound may a added to the solution of lipid and polymer before drying or it may be blended to into the dried lipid polymer powder to form a uniform mixture. The compositions a be wdered for filling into hard gelatine capsules or they may be formed m y Po into granules for tabletting.
--- prie>d Ratio APPnnnce After E!nmplc Sample Dmos Starch sodium octcnYL~"ccinatc VP200I SW ch sodium Pale yellow very cttspY
octrnykuccioatc ( 1:1 ) solid VP200/ modified starch ( l-2) Pzlc Yellow very crispy -_ _-WA
32 .-- ,. ...._ VP2001 hish amylosc Ydlow cruz>chY slid -- Lru m t' rnodt ficd staren t r ~ r l5 ~Natioual Stanch and Chnttica) Company Examples 34- 36 Examples 34-36 illustrate the use of polymers generally for hardening a li id widely used in food applications- Several different grades of gelatine were P
orated with de-oiled lecithin, which contains a mixture of neutral incorp s holi ids, charged phospholipids and glycolipids. The solids were prepared pho p P
usin various concentrations of polymer in aqueous media. The lipid was g dis ersed in water without ethanol, before addition of the polymer to give a P
viscous dispersion. In all cases, removal of the water resulted in crispy com sitions that could be further comminuted to give free-flowing powders or p°
ules. The powdered lipid polymer compositions could be used in place of gran .
rdin de-oiled 3ecithin in various applications, or they could be employed to 0 ~' c active compounds either in molecular association or dispersion with the liquid polymer.
Sample Dried Ratio Appeanpce After Example Drnited ItcithidGclatin Drytng I :1 Crispy 61m Alhali hydrolysed gelatine Bloom strrn h 200 35 Acid hydrolysed gdatinc I: i Cusp film gloom strrn h 150 _ . liydrolyscd gdatinc !:1 Crisp. battle film S .
Examples 3'1- 39 The following examples further illustrate the utility of the invention in rendering membrane lipids in combination with over poly' lipids hard and to comminutable to extend their use generally, pa~cularly in oral dosage forms-In exam les 37 - 39 the lipid was initially heated gently on a hot plate and the P
aqueous polymer solution was added ~d stirred to produce a homogeneous sus nsion_ Removal of water from the slurry was wed out in a vacuum oven at Pe 50°C until the weight of the composition remained constant- A hard, crushable solid lymer lipid composirion was formed in each case. As in the previous Po examples ~ active compound may be added to the slurry before remora-1 of water or it may be blended into the solid polymer lipid powders after removal of water.
pried Ratio Appearance After Drying ( i idl olvmer Ecample Sample 37 Phosph~tidylchoiinc and saccitzrosc PClsxcharosc monop~imit:ud Otrwhitc hard composition mono almitatc CMC ( 1:1:21 3x VP200 acrd glYcaYimonocaPtYlatc VP200/ glycerylmonocaprylate Pale yellow friable solid l maize starch (0_1:1 41 Egg phospholipid 60 % PC zTrd PolYglYccTy1 EPCJpoIY glYccO'1 m°n°°IntdCMC Pale ydlow crushable solid (0.5Ø3:1 _0) 39 monoointc pCT/G B99/Od070 Examples 40 - 45 The following ex~ples typically illustrate the utility of the invention in rendering various polar lipids and combinations thereof hard and comminutable to both lipophilic and hydrophilic compounds. Examples 40 -~41 are solid lipid 5 ~T
1 er compositions composing lipophilic compounds, that may be powdered P° Ym and filled into hard gelatine capsules or with the aid of suitable excipients com ressed into tablets. Examples. 42- 43 are solid lipid polymer compositions P
com rising hydrophilic compounds. In example 40 the active, lipid and PolYm~
P
were dissolved in dichloromethane to produce a clear yellow solution. The to ichlorornethane Was removed from the solution under vacuum to produce a solid d of er composition containing flurbiprofen_ In example 41 beclometha.sone P n"
ro innate was dissolved in an ethanolic solution of Soya PC. The ethanolic dip p solution was added to an aqueous dispersion of carboxy ~nylp°lyn'er and sodium x ethylcellulose. After drying, a ~sPy Yellow solid composition of BDP
t s ~o ym was obtained. This composition could be further processed to produce a free awin owder or granules. Examples 42- 44 were prepared by dispersing the fl gp 've and lipid in an aqueous polymer solution. After drying, a hid, ~hable acri solid polymer lipid composition was formed in each case. In example ~, acetic -d was added to the polymer solution to produce a solution of chitosan. In 20 act le 45, the cyA, EPC ~d methacrylic copolymer were dissolved in ethanol.
examp A solid lipid polymer composit<on of cyA was obtained when the solvent was removed.

pried ApP~~cc After Rstio Drying Lipids)Polymcr(s) Adivd E:ampleActive Li idl compound olvmn colt yellow solid htl Sli 1:10:10 y g VP 200 Eudragit EI00 Flurbiprofrn Yellow czzWY
~~

Carboxy vinyl 1:20:25:20 polymerlsodium 41 BeclotnethasonesY~ c~ox ~ 1 cellulose PC Ftiablc ortnge solid di innate Low molecular 1:5:10 wtchitosan 42 ChlotitczidincDrnilcd OfT white wispy solid di htconntcixithinC~'xY ~Y cellulose1:50:20 43 Panetr~tmDeoilcd OCfwhrtcfriablcsolid lecithin btodificdstarch0.1:1.2 Yellow crispy solid 44 VP145 1"I~uCryc xid O.I:OS:01:0_2 copolymer i5 Cy ~
(60%P~

~ ~
I,plyglycerol PC'TIG B99/04070 The compositions in the examples may be filled into hard gelatine capsules or the like or alternatively, they may be compressed into tablets or the Iike_ presentation S
'fhe waxy nature of lipids has previously been a general obstacle to the use of effective amounts of lipid in solid dosage forms, which may be one of the reasons why more advantage has not been taken up to now of the capacity of lecithin to improve drag delivery. The use of polymers has now been shown to increase the hardness and modify the processing characteristics of Lipid, which dramatically increases the potential use for such formulations. The present formulations can be incorporated into a number of delivery systems including solutions, suspensions, tablets, capsules, gels, suppositories and pessaries as well as a free powder or granules. The greater potential lies, perhaps, in compressing IS the powder into a tablet or filling it into a hard gelatine capsule for oral delivery.

Claims (23)

-1-

1. A composition for delivering a biologically active compound comprising:
(a) a biologically effective amount of at least one biologically active compound;
(b) a mixture of lipids in which the biologically active compound is dissolved or dispersed, said mixture comprising as first component a single chain amphipathic lipid which is a monoacyl derivative of a phospholipid, glycolipid, sphingolipid or a polyethylene glycol derived monoacyl phospholipid and as second component at least one double chain amphipathic lipid which is a bilayer forming phospholipid;
and (c) a polymeric material associated with and hardening said lipid or lipids so that they become friable or crushable at ambient temperatures, and selected from natural gums and derivatives thereof, gelatine, partially hydrolysed gelatine, celluloses, starches, modified starches, charged pharmaceutical polymers and polyvinylpyrrolidone.

2. The composition of claim 1, wherein the polymeric material is a salt of carboxymethylcellulose, alginic acid or a salt thereof, a starch modified with anionic groups, agar, carrageenan, gum arabic, gum tragacanth, gum xanthan, pectin, carboxypolymethylene, a methyl vinyl ether/maleic acid copolymer, a methacrylic acid copolymer, an ammonio methacrylate copolymer, a basic polymethacrylate,or chitosan,

3. The composition of claim 1 or 2, comprising an enzyme digested lecithin.

4. The composition of claim 3, comprising 60-80 mol % of monoacyl lipid.

5. The composition of any preceding claim, wherein there is present at least wt % of the polymer based on the weight of said base composition.

6. The composition of any preceding claim, further comprising a sugar.

7. The composition of any preceding claim, further comprising a polyol, sucrose ester or polyglyceryl ester of a higher fatty acid or another polyol ester of a higher fatty acid.

8. The composition of any preceding claim, wherein the ratio by weight of the lipid to the active compound is from 40:1 to 1:40.

9. The composition of any preceding claim, wherein the active compound is present in molecular dispersion in the lipid.

10. The composition of any of claims 1-8, wherein the active compound is present as discrete particles in the composition.

11. The composition of claim 10, wherein the size of said particles is not more than 1µm.

12. The composition of any preceding claim, wherein the biologically active compound is cyclosporin A, Taxol, tacrolimus or a rapamycin.

13. The composition of any of claims 1-11, wherein the biologically active compound is insulin, calcitonin or heparin.

14. The composition of any of claims 1-11, wherein the biologically active compound is ubiquinone, a tocopherol, a carotenoid or a bioflavenoid.

15. The composition of any preceding claim, which is of powder of size 50-2000 µm.

16. The composition of any preceding claim, which is of powder of size 50-1000 µm.

17. The composition of any of claims 1-14, which is of granules of size 1-5 mm.

18. A method for making the composition of any preceding claim, which comprises dissolving or dispersing the ingredients in a solvent and removing said solvent.

19. The method of claim 18, wherein the lipid and biologically active compound (if present) are dissolved in ethanol, the polymer is dissolved in water, the aqueous and ethanolic solutions are mixed, and the mixture is dried.

20. The method of claim 18 or 19, comprising the further step of comminuting the composition after the solvent has been removed.

21. The method of claim 20, comprising the further step of forming siad comminuted composition into a tablet.

22. The method of claim 20, comprising the further step of filling said comminuted composition into a capsule.

23. The composition of any of claims 1-19 which is a powder that when stored in a glass container remains free flowing after storage for 3 months at 40°C and 75%
relative humidity.