CA2119253C

CA2119253C - Medication vehicles made of solid lipid particles (solid lipid nanospheres-sln)

Info

Publication number: CA2119253C
Application number: CA002119253A
Authority: CA
Inventors: Stefan Lucks; Rainer Muller
Original assignee: Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Current assignee: Jagotec AG
Priority date: 1991-09-18
Filing date: 1992-09-16
Publication date: 1998-11-03
Anticipated expiration: 2012-09-16
Also published as: EP0605497B2; AU672177B2; JP2683575B2; CZ289253B6; WO1993005768A1; HU9400779D0; GR3030291T3; AU2561592A; KR0141504B1; DE59205783D1; DK0605497T3; JPH06510772A; ATE135567T1; GR3019750T3; ES2085035T5; CA2119253A1; CZ59694A3; EP0605497A1; ES2085035T3; HU227680B1

Abstract

The invention relates to a drug carrier which comprises particles of lipid or lipid-like (lipoid) material or mixtures thereof which have a diameter of 10 nm to 10 µm and which are solid at room temperature. On account of its solid core, the drug carrier allows a controllable liberation of active substances over a longer period of time and the incorporation of hydrophilous medicinal agents into the solid core. Furthermore, the drug carrier makes a relatively quick degrading possible at which no toxic by-products are produced.

Description

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Dr~ carrier co~ct;n~ of solid lipid E~articles - Solid lipid nanospheres The invention relates to a drug carrier, its dispersion in a watery me~ m, a method to produce it, as well as its use. It concerns in particular a drug carrier consisting of lipid or lipoid particles.

In the field of m~Aicin~l agents there is a continuous search for carriers which allow drug application in various ways, i.e. carriers which are available in a form that permits the respective drug to be ~mini~tered as deemed most suitable, e.g. in an intravenous, i,l~ ricular, intramuscular or subcutaneous manner.

Carriers are known which consist, e.g. of solid microparticles, microspheres and mircrocapsules (mean m~ter in the micrometer range), as well as nal~pa.~icles and nanocapsules (mean ~ meter in the nanometer range). Microparticles and nanoparticles consist of a solid polymer matrix. With respect to microcapsules and nanocapsules, liquid or solid phases are enclosed by film-forming polymers. Such particles consist of or have coatings of polymers, such as polylactides (PLA), polylactide-glycolides r ' ~

2 ~ 3 (PLA/GA) or polyalkyl cyanoacrylates. Polylactide and polylactide-glycolide as particle matrix and as coatings have, however, the disadvantage of degrading only very slowly, i.e. the degradation takes weeks up to months. Multiple applications of a drug with such a carrier lead to an a~cum~ Qn of polymer in the ~ -l and possibly cause toxic effects. Although particles based on polymers, such as polyalkyl cyanoacrylates, metabolize up to 80% in the or~ lll within a period of 24 hours, toxic form~ ehyde is set free during the decolll~osilion. To produce the polymeric particles, carbon hydrogen chlorides, such as dichlo. Illh~ n~, have to be used as solvents for the polymer, and these solvents in turn are toxic on their part (T.R. Tice and D.ll. Lewis, Microencapsulation Process, US-PS 4 389 330).
Furthermore, on account of their size, microparticles may cause embolisms when injected intravenously, and therefore one usually refrains from this procedure. Another disadvantage of polymeric particles is the fact that when sterilizing in an autoclave, the glass temperature is eYcee~1~1 thus resulting in an aggregation of particles. Such drug carriers or drugs can therefore not be sterilized in this manner and have to be subjected to the disadvantageous procedure of gamma irradiation.

Also known to serve as drug carriers are fat emulsions. Fat emulsions are oil-in-water emulsions in which the dispersed (inner) phase is liquid. In the trade lilelalule such fatty emulsions are also referred to as "lipid microspheres", and highly disperse fat emulsions with a mean particle size in the nanometer range are also called "nano-emulsions" (ll.G. Weder and M. Muet~h, Eur Pat. EP 90-810436, June 1990).
These fat emulsions comprise two liquid phases. After diluting with body fluids, fat emulsions set incorporated medicinal agents free within a relatively fast time (e. g. after injection into the blood). The t ~50%) is in the 30 to 60-second range, which is correlated to the rate of ~iffu~ion of the m~licin~l r~

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'_ agents in the oil that is of relatively low viscosity. Furthermore, the liquid, dispersed phase of the fat emulsions (= oil) will be completely metabolized in the body within a few hours, which liberates from the oil also extremely lipophile substqn~es. Such quick liberations may also lead to the so-called pealcs of the medicinal agents in the plasma so that toxic side effects are possible due to this brief overdosing.
In addition, the loss of active substyqnre before it reaches the target organ is relatively large when passively aiming at macrophages of the liver and spleen.

Through P. Eldem, P. Speiser and A. Hincal, Pharmqceuti~ql Research 8 47-54 (1991) micropellets on a lipid basis have become known, the mean ~ meter of which again is in the micrometer range.

Known are also drug carriers in which liposomes or subst~ncec which resemble or are analogous to liposomes, such as niosomes, having an aqueous liquid core, are enclosed by one or several phospholipid double membranes.

Furthermore, subparticulate or semiparticulate systems are known in which substances are dissolved with the help of solving agents, such as tencid,~s, to an extent that micells or mixed micells will form.
What they are here are no longer dispersions but already solutions.

Therefore, the object of the invention is to make available a drug carrier which can form a dispersion of particles in an aqueous m~ium, in which the particles are solid at room temperature and can be degraded biologically, and where, in addition, the particles consist of components which have low or no toxicity at all. Furthermore, the object in producing the drug carrier is to make toxic exipients, A

2 ~ 3 such as halogenated organic solvents (dichiormpth~ne or similar) nnnecess~ry. In addition, a method to produce this drug carrier shall be made available.

The invention solves this problem, as set out in Claim 1, by a drug carrier that comprises particles consisting of lipid or lipid-like (lipoid) subst~nre~, or a mixture thereof, which have a ~ mP.ter of 10 nm to 10 ~4m and which are solid at room temperature.

Preferred forms of this drug carrier are the subject of the patent claims.

With respect to the drug carrier it concerns particles that are solid at room temperature (i.e. about 20~C) and the size of which is in the nanometer range. Such particles can be defined as "solid lipid nanospheres" (SLN). These particles can be dispersed in an aqueous mP~lium, thus resulting in a solid/liquid dispersion. The particle size of the dispersed phase is in the range of ~ 10 nm up to a few micrometers (about 10 ~m). The average particle size (di~mp~ter determinPA by photon correlation spectroscopy) is predominantly in the 100 to 1000 nm range and especially in the 100 to 800 nm range.
By selecting suitable processing parameters and by choosing appropliate exipients (e.g. a higher tenside concentration), it is possible to make the SLN smaller than 100 nm, especially in the 40 to 80 nm range.

The SLN consist of lipid or lipid-like substances which can be degraded by the o~ like fat from foodstuffs. The degradation of lipids occurs at a faster rate than the decomposition of synthetic polymers such as PLA, PLAIGA. Another advantage is that in the degradation or in the metabolization of lipids no toxic metabolites are produced, as is the case in particles of a polyalkyl cyanacrylate base. Reference is made in this connection to the taxicology of fatty emulsions used in part;~ dl nutrition since the l950's.
Since in SLN it concerns solid, lipid particles with a relevantly high viscosity, the rate of difflision and liberation of an active substance embedded therein is reduced. Thus, conL,~ to the fat emulsions consL,lillg of a liquid-dispersed phase, it is possible to achieve a controlled liberation over a longer period. On account of the longer liberation period, the formation of plasma peaks of the respective active ~lbst~nce is prevented and side effects, which occur as a result of such peak value~" are elimin ~ l Due to the delayed liberation, the loss of active substance after application and before reaching the respective target organ is smaller than in fat emulsions in which the active subst~nc~ are liberated co,lll)ala~ively fast.

The active substance or substances are dissolved or dispersed in the lipid or lipid particles. Furthermore, the active substances can be adsorbed at the surface of the particles. On account of the solid matter character it is also possible to incorporate in the lipid or lipid phase hydrophilic s~1hst~nres in the form of an aqueous solution of the active suhst~nre. After incorporating and subsequently dispersing the obtained SLN in an aqueous dispersion medum, a WIFIW system (i.e. water-in-fat-in-water) is produced.
On account of its solid aggregate state, the lipid core incorporates the aqueous drug solution better than it is possible in colll~able, multiple emulsions of water-in-oil-in water (W/01W).

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Another advantage of the solid, lipid nanospheres is the fact that, in contrast to the polymeric particles, they can be sterilized in an autoclave without causing an aggregation of the particles. In this way the dis~l~dll~d~ ~ cormected to gamma irradiation can be avoided.

Contrary to microparticles of the microm~ range, the SLN can be injected ~l~la~/el~ously without dif~lculty and without the risk of embolism due to their small particle size in the n~nr)mP.ter range. When producing the SLN, no toxic adjuvants have to be used such as e.g. slightly volatile solvents of chiorohydrocarbons .

The drug carrier according to the invention can be produced in the following manner:
1. by dispersing the inner phase (of the lipid or lipoid) in a melted or softened state. The dispersing is carried out above room temperature and can be achieved by various procedures such as, for example, the methods described below;
2. by dispersing the solid inner phase in a solid state. For this purpose, the solid phase is fmely broken down and dispersed in water or in an aqueous meAillm Prior to this, the dispersed lipid or lipoid core, which is solid at room temperature, WdS loaded with one or more medicinal agents. This can be achieved by dissolving or dispersing the active substance in the lipid/lipoid, by adsorbing the active subst~nce at the surface of the lipid/lipoid, or by dispersing it in the lipid/lipoid in the form of an aqueous solution.

As dispersed phase, lipids and lipoids can be used in the widest sense as individual compounds or as ules. Examples of these include the following: natural or synthetic triglycerides or IlliALufes thereof, mono and diglycerides alone or in Illi~Lules thereof or with e.g. triglycerides, natural and synthetic waxes, fatty alcohols, including their esters and ethers, as well as lipid peptides. Especially suitable are synthetic monoglycerides, diglycerides and triglycerides as individual substq-n~es or as Illi,~Lures (e.g. hard fat), glycerin trifatty acid ester (e.g. ~lyceliilLIilaurate, glycelh~lllylis~Le, glycerinp,q-lmitqte, glycerinstearate and glycerinbehenate) and waxes such as, for example, cetylpqlmitqte and cera alba (bleached wax, DAB 9).

The content of the inner or lipid phase, related to the basic p~ lion, is 0.1 to 30% by weight and pr~r~"~ly 1 to 10% by weight.

Should it be nececcqry to use dispersion-stabilizing additives to produce stable dispersions, these can be incorporated to stabilize the particles in the form of pure substances or in the form of mixtures. The quq-ntitity to be used in relation to the total weight of the watery dispersion ranges in per cent by weight from 0.01 to 20 and preferably from 0.5 to 5. The following subst~q-nc~s come into consideration as stabilizing agents:

a) tensides, particularly ethoxylated sorbitan fatty acid ester, blockpolymers and blockcopolymers (such as e.g. poloxamers and poloxamines), poly~lycelill ethers and polyglycerin esters, lecithins of various origin (e. g. egg-lecithin or soya-lecithin), chPmic~lly modified lecithins (e.g. hydrated lecithin), as well as phospholipids and sphingolipids, ll~iAlules of lecithins with phospho lids, sterols (e.g. cholesterin and cholesterin deli~atives, as well as stigm~tPrin), esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols (e.g.
saccharosemonostearate);
b) sterically stabilizing ~ k"l~ncP,~, such as poloxamers and poloxamines (polyoxyethylene-polyoAyl,rop~lene-blockpolymers), ethoxylated sorb itan fatty acid ester, ethoxylated mono- and diglycerides, ethoxylated lipids and lipoids, ethoxylated fatty alcohols or fatty acids, and c) charge enh~ncing stabilizers or charged compounds such as dicetylph--sph~te, phosphatidyiglycerin, as well as saturated and unsaturated fatty acids, sodium cholate, sodium glycolcholate, sodium taurocholate or nliA~ures thereof, amino acids or antiflocc~ nt~ such as sodium citrate (see J.S. Iucks, . W. Muller, R. II. Muller, mt. J. ph~rm~reutice 63 183-188 (1990));

d) viscosity increasing substances such as cellulose ethers and cellulose esters (e.g. methyl cellulose, hydroxyethyl cellulose, hydloAy~n~yl cellulose, sodium carboxymethyl cellulose), polyvinyl derivatives, such as polyvinyl a1cohol, polyvinyl pyrrolidon, polyvinyl acetate, algin~tP-~, polyacrylates (e.g. CARBOPOLn'), ~nth~nes and pectins.

The charge enh~ncing stabilizers are incorporated, if necP~ry, in relation to the basic preparation, prt;Çelably in a quantity of 0.01 to 10% and most pler~.dl)ly in a quantity of 0.05 to 2%. The viscosity increasing substances are likewise incol~ d, if nPceC~ry, in relation to the basic pr~aldion~ pler~ldbly in a quantity of 0.01 to 10%, and even more prt;rt;lably in a quantity of 0.1 to 10% and most pr~relable at 0.5 to 5%.

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As outer phase (continuous phase, dispersion medium) water, aqueous solutions or liquids miscible with water, such as glycerin or polyethylene glycol, are used. The aqueous solutions can be nonisotonic or isotonic for this purpose. To be taken into consideration as watery solutions are llli~lures of water with one or several other components such as the following: glycerin, nl~n--se, glucose, fructose, xylose, trehalose, mannitol sorbitol, xylitol or other polyols such as polyethylene glycol, as well as electolytes such as sodium chloride. These components are then put proportionately into the basic plepdrdlion in a quantity of 0.1 to 50% and prererdbly 1 to 30%.

The SLN are produced generally by dispersing the inner phase (the lipid or lipoid) into the outer phase (water, aqueous solution or a liquid that is miscible with water) at above room temperature ( > 20~C).
When dispersing it is plereldble to avoid using ultrasonic probes in order to prevent co~ A'ion by metal particles (e.g. Ti). The te~ )eld~ure shall be selected so that the substance to be dispersed is in a liquid state or at least in a softened state. Thus, many lipids are dispersed at 70 to 80 ~C. The production is usually accomplished in two stages:

1. by making a pre-dispersion, e.g. with a stirrer or with a rotor-stator-disperser (e.g. ULTRA
TURRAXTY). If necessary, one or several dispersion-stabilizing substances are added;

2. by subsequently dispersing in a high-pres~ure homogenizer at an increased pres~ure (e.g. a cap homogenizer, such as APV Gaulin or French Press, a jet-stream homogenizer such as the microfluidizer). In systems with good dispersible capacity, step 1 can be eli,--ilu~

Tenside-free SLN is produced by dispersing the lipid or lipoid phase in a watery solution which contains one or several viscosity increasing substances either alone or in co~ lion with other s~ st~nres, such as sugars, sugar alcohols, especially glucose, rn~nn(-se7 trehalose, mannitol, sorbitol, as well as others.
Furthermore, it is possible to use a co-~indlion of the viscosity increasing subst~nre(s) or the combination thereof with sugars or sugar alcohols, or in a further co,-,l,h~lion with charged co~ uullds.
Suitable charged compounds, for example, are the following: sodium citrate, sodium pyrophosphate, sodium sorbate.
The active substance(s) can be incorporated by various methods, as for example:

1. by dissolving the active substance in the inner phase;

2. by dissolving the active subst~nre in a solvent that is mixable with the inner phase and by adding this solutionto the inner phase. The solvent will subsequently be partially or completely removed, if required;

3. by dissolving the active substance in the inner phase (e.g. by dispersing a solid matter or by controlled ple.;ipi~lion of the active subst~rlce in the inner phase);

4. by dissolving the active substance in the outer, watery phase (e.g. amphiphilous subst~nres) and enrlosing the active agent during the production process in a particle-stabilizing tenside film;

5. by adsorption of the active substance on the surface of the particles;

c~ Ja 6. by dissolving the active subst~n~e in the lipid/lipoid phase by means of a solubilifing agent (e.g.
a blockcopolymer or a sorbitan fatty acid ester), and subsequently dispersing the lipid/lipoidphase in order to produce the preliminary dispersion. The active subst~nce is then present in the SLN
as a solid solution;

7. by incorporating aqueous solutions of the active substance into the lipid/lipoid phase and subse~luently dispersing the lipid/lipoid phase in order to make the preliminary dispersion, thus producing a WIFIW system which is analogous to the multiple emulsions.

The sterilization can be accomplished according to the procedures outlined in the pharmacopeia, as for example by means of autoclaves (121 ~C, 2 bar, DAB 9) or according to other recognized procedures.

The realms of use of the drug carrier according to the invention with the solid liquid nano spheres are manifold. For example, it can be used for the following drug applications:
p~ellleldl, enteral, pulmonary, topical (nasal, dermal, intra-ocular) and in body cavities.

With respect to the parell~elal application, it concerns in particular the following:

1. Intravenous a l",i~ , dtion (targeting the liver, spleen and bone marrow, particles circulating in the blood and the controlled liberation of active substances, such as peptide drugs, cytostatics, immlln~stim~ nt~, growth factors, such as the colony stimul~ting factor (regulation of leucocytes) and the growth factor.

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2. IntrAm~l~cul~r A~ ion depot dosage forms for PYtended or prolonged release of the active substances, e.g. peptide drugs or hormones).

3. Intra-ar~ricular a~,h~ tion (e.g. for ~ntirheumAti~s and immunosuppressives for arthritis).
4. Intracavital ad...i~ ldion (e.g. for cytostatics and peptide drugs for forms of cancer in the peritoneum and in the pleura cavity) and for the 5. subcutaneous a~ l dion (e.g. slow release of the drug for liy~o~ ics in skin cancer).

The enteral forms of application are suited ~speci~lly to the following:

1. incull,ol~ion of lipid-soluble vitamins;
2. lylllpha~ic adsorption (e.g. drug-targeting of cytostatics to the lymph nodes):
3. pre~nt~ion of antigens (e.g. oral i,.".. ~ni,A1ion with the help of Peyer' 5 plaques), and 4. uptake of peptide medicinal agents with the help of M-cells.

As pulmonary forms of application, especially the following come into consideration:

1. aerosols, dosing aerosols (spraying of the aqueous SLN-dispersion), 2. imtillAtion of the dispersion.

Examples of topical application,s:

1. dermatological drugs for application of e.g., corticoids and antimycotics;
2. Eye drops or eye gels, e.g. for B-blocker, but also for 3. cosmetics analogous to the liposomal prel,~dions.

~, _ 13 Examples of drn~ to be incorpor,qt-p~l into the SLN (,q,~ salt, ester. et_er or in a liberated form) Analgetics/Antirhel~m~ir~
Morphine, codeine, piritamide, fentanyl and fentanyl dt;livdi~eF" levomPthq-~lon, tramadol, diclofenac, ibuprorell, indo...eli..~ , naproxen, piroxic m, pPni~ qminP

Anti-allergics Phe~i,~"ine, ~limP.tindPn, terfP-nq~linP, ~l;;"~i;Gol, loratidine, doxylamine, meclozine, bamipin, clemastin Antibiotics/Chemotherapeutics from these: polypeptide . ntibiotics such as colistin, polymyxin B, teicplanin, vancon,ycill;
qnflmqlqrial such as quinine, halofantrin, mefloquine, chloroquine; Vil.l,~tiCs such s ganciclovir, foscarnet, zidovudin, aciclovir and others such as dapson, fosfomycin, flirqflingin, trini~t,opli", Anti-epileptics Phenytoin, mesl-~irnidP~, ethosuYirni~le, prirnidon, phenobarbital, vaiproin acid, ca,ba,~ epin, clon~q,7eFqm ~r It' Antirnycotics a) internal:
Nystatin, n~ ycin, amphotericin B, flucytosine, miconazole, fluconazole, itraconazole b) PYt~P-rnql~ in addition:
Clotriniazole, econazole, tioconazole, fenticonazole, birundLole, oxiconazole, ketoconazole, isoconazole, tolnaftate Corticoid (internal) Aldosterone, fludrocortisone, betqm~-tq~one~ deYq~n~tq~one, triamcino lone, fluocortolone, hydro~ycortisone, prednisolone, prednylidene, cloprednole, ~l~ ylplednisolone Dermatics a) Antibiotics:
Tetracyline, elyll~olnycin, neomycin, gelllalllycin, clindamycin, framycetin, tyrothricin, chloretetracyline, mipirocin, fusidin acid b) Virustatics as above, but in addition:
Podophyllotoxin, vidarabine, llolllAIllA~1inP, c) Corticoids as above, but in addition:
Anicinonide, llupredni~lp~n~ llciomptp~on~ clobetasol, diflorason, halcinonide, fluocinolone, clocortolone, Ill~ .t.~on, difluocortolone, flurandrenolide, halometason, desoximetason, fluocinolide, fluocol~ lyl, flupreniden, prednicarbate, desonide '' 2119253 . .~.. .

Diagnostics a) radioactive isotopes such as Te99m, Inlll or I131, covalently bound to lipids or lipoids or other molecules or in complexes b) highly substituted iodine-cont~inin~ compounds such as, e.g., lipids Haemostyptics/Antihaemorrhagics Blood clotting factors VIII, IX

Hypnotics, Sedatives Cyclobarbital, pentobarbital, phenobarbital, methaqualone, benzodiazepines (flurazepam, midazolam, nitrazepam, lormetazepam, flunitrazepam, triazolam, brotizolam, temazepam, loprazolam) Pituitary horrnones, hypothalamic hormones, regulatory peptides and their inhibiting agents Corticotrophin, tetracosactide, choriongonadotropin, urofolitropin, urogonadotropin, somatropin, metergoline, bromocriptin, terlipressin, desmopressin, oxytocin, argipressin, ornipressin, leuprorelin, triptorelin, gonadorelin, buserelin, nafarelin, goselerin, somatostatin 211~3 ~ . .

Immunotherapeutics and Zytokine Dimepranol4-acetate amido benzoate, thymopentin, a-interferon, B-interferon, y-interferon, filgrastim, interleukin, azathioprine, ciclosporin Local Anaesthetics internal:
Butanilicaine, mepivacaine, bupivacaine, etidocaine, lidocaine, articaine, prilocaine, external, in addition:
Propipocaine, oxybuprocaine, tetracaine, benzocaine Migraine Agent Proxibarbal, lisuride, methysergide, dihydroergotamine, clonidine, ergotamine, pizotifen Anaesthetic Agent Methohexital, propofol, etomidate, k~.t~mine, alfentanil, thiopental, droperidol, fentanyl Parathyroid Gland Hormones, Calcium Metabolism Regulators Dihydrotachysterol, calcitonin, clodron acid etidron acid .., Opthalmics atropine, cyclodrin, cyclopentolate, homatropine, tropicamide, scopolarnine, poledrin, edoxudine, trom~nt~tline, aciclovir, acetazolamide, diclofenamide, carteolol, tirnolol, metipranolol, betaxolol, pindolol, befunolol, bupranolol, levobunuol, carbachol,pilocarpine, clonidine, neostigmine idouridirI~, Psycho-Drugs Benzodiazepines (lorazepam, diazepam), clomethiazol Tyroid Gland Therapeutics 1-thyroxin, carbimazole, thi~m~701e, propylthiouracil Serums, Immunoglobulins, Vaccines a) Tmml~noglobulins in general, and specifically such as heptatitis types, German measles, cytomegaly, rabies, FSME, chickenpox/shingles, tetanus, rhesus factors b) Tmml-noserums such as botulism-antitoxin, diphteria, gas gangrene, snake poison, - scorpion poison c) Vaccines such as influenza, tuberculosis, cholera, diphteria, hepatitis types, FSME, German measles, haemophilus influenzae, measles, neisseria, mumps, poliomyelitis, tetanus, rabies, typhoid ~119~.53 .", . .

Sex hormones and their inhibiting agents Anabolics, androgens, anti-androgens, gestagens, estrogens, anti-estrogens (tamoxifen, etc.) .

Cystostatics and Metastasis Inhibitors a) Alkylants such as nimustine, melphalane, carrnustine, lomustine, cyclophosphamide, ifosfarnide, trofosfamide, chlorambucil, busulfan, treosulfan,prednimustine, thiotepa b) Antimetobolites such as cytarabine, fluorouracil, methotrexate, mercaptopurine, tlog~amne c) Alkaloids such as vinblastine, vincristine, vindesine d) Antibiotics such as aclarubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, plicamycin e) Complexes of secondary group elements (e.g. Ti, Zr,V, ~b, Ta, Mo, W, Pt) such as carbo-p~atinllm, cis-platinum and metallocene compounds such as titanocendichloride f) Arnsacrine, dacarbazine, estramustine, etoposide, ~ly~lluxy~lr mitoxanthrone, procarbazine, temiposide g) Alkyl amido phospholipids (described in J.M. Zeidler, F. Emling, W.
Zimmermann and H.J. Roth, Pharmacy Archives, 324 (1991, 687) h) Etherlipids such as hexadecylphosphocholine, ilmofosin and analoga, describedin R. Zeisig, D. Arndt and H. Brachwitz, Pharmacy 45 (1990), 809-818.

The invention is explained in greater detail by the following examples.

Exam~le 1 10.0 g cera alba (bleached wax) 2.5 9 poloxamer 188 (polyoxyethylene-polyu~yl,lul,ylene-blockpolymer) 0.1 g dicetyiphosphate 87.4 g water for injection purposes Cera alba and dicetyiphosphate were heated to 70 ~C and mixed with a solution of POLOXAMER~ 188 in water for injection purposes with a solution of poloxamer 188, which was likewise heated to 70~C. The ,l,ixlure was predispersed at 70~C with the help of an ULTRA
TURRAX~. The resulting prelimin~ry dispersion was subsequently put through an APV Gaulin high-pressure homogenizer which had been ~t;"~pel~lure adjusted to 70~C (5 cycles with 500 bar).
A SLN-dispersion was ~tt~ined with a mean rli~mp~ter of 216 nm. The polydi~ y index, serving as measure for the width of the particle size distribution, was 0.143 (l)CS - photon correlation s~ loscol)y). All particles were smaller than 6.0 ,um (measured with a Sympatek laser diffractometer meter).

Example 2:
10.0 g cetylp~lmit~tP
2.5 g poloxamer 188 87.5 g water for injection pu~oses The production was done as described in example 1. The mean ~ metpr was 215 nm and the polydispersity index was 0.131 (PCS-data). All particles were smaller than 4.2 ~m (laser diffractometer) .

Example 3:

10.0 g cetylpalmitate 2.5 g lipoid S 75 (soyalecithin with 75 % of phosphatidylcholin) 0.1 g dicetyiphosphate 87.4 g water for injection purposes The production was done as described in example 1. However, lipoid S 75 was dispersed in the heated lipid phase. The mean (1i~m~.ter was 183 nm, and the polydispc~ y index was 0.1333 (PCS-data). All particles were smaller than 8.6 um (laser diffraction meter).

,~

2I-192~3 Example 4:

10.5 g glycerintrilaurate (Dynasan(R) 112) 2.5 g poloxamer 188 87.5 g water for injection purposes The production was done as described in example 1. The mean diameter was 199 nm and the polydispersity index was 0.180 (PCS-data). All particles were smaller than 7.2 ~m (laser diffraction meter).

Example 5:

10.0 g cetylp~lmit~te 2.5 g poloxamer 188 0.5 g dicetylphosphate 87.0 g water for injection purposes The production was done as described under example 1. The char~tPri~tic data before and after the autoclaving subst~nti~tes the applicability of the sterilization method.

mean polydis~ y all particles ~i~meter index smaller than before st~rili7~tion 215 nm 0.131 4.2 ~m after st~-rili7~tion 214 nm 0.109 3.0 ,um Example 6:

As a model drug, 0.25g of tetracaine base were incol~ldted in p~ )aldtion No.5.

The production was done as described in example 1. The mean ~i~mP~ter was 218 nm and the polydispersity index was 0.186 (PCS-data). All particles were smaller than 10.2 ,um (laser diffracto meter).

The drug inco.~ldlion rate was 92.8~.

21 1-g253 Example 7:

As a model drug, tetracaine base was incorporated in the following preparation:

10.0 g glycerin trilaurate (Dynasan 112) 5.0 g lipoid S 75 tetracaine base of 0.1 g, 0.5 g, 1.0 g or 2.0 g to 100.0 g water for injection purposes The production was done as described in exarnple 1. However the high-pressure homogenization was carried out at 1500 bar (three cycles). The following values were achieved as mean diameter (PCS-data).

Drug Content PCS-diarneter (related to lipid phase) (nm) 1% 103 5% 102 10% 101 20% 125 E~ample 8:

The prcpar~lions, as mPntio~P~ under example 7, were autoclaved (A 121) according to DAB9.

Drug Content PCS~ mP,ter PC S~i~metP,r (related to lipid ph~cP) before autoclavin~after autocavin~

1% 103nm lOlnm 5 % 102 nm 102 rim 10% 101 nm 9S mn When active s~hst~ncP,c are used which are sc,~i~iv.e to hydrolysis, the particles can also be Iyophilized or dried by spraying.

Example 9:
10.0 g glycerintrilaurate (Dynasan 112) 5.0 g lipoid S 75 O.S g lcllacahle base 84.5 ml aqueous glucose solution (30% mIV) The production was done as described under example 1. However, the high-pres~ulc homogenization was carried out at 1500 x105 pa (1500 bar) (three cycles). As mean diameter (PCS-data), the following values were obtained before and after lYorh~

Mean diameter Pol~di"~.~ily index before Iy~phili ~-~n90 nm 0.277 after Iyop~ili7P~481 nm 0.289 r~
D

~r ~ 25 As another drug, t_e active ' -e hexad~y r' ~ ~hnlin (HPC) was iilCO.~ ' in a model ~l~r nn F _'~ 10:

10.0 g ol~ (Dynasan 112) 5.0g F- ~Y 188 0.1 g hP--' yilJh~J~o '-' 84.9 g water for injection purposes The production was done as ~ccrihed in example 1. The attained SLN~ ' had a mean PCS diameter of 178 nm. The polydii"~. ,ily index was 0.1653. All particles were smaller than 3.6 ,um (laser ~liffra t ). By varying the tenside content or the tenside CO~~ it was possible to produce SLN~is~r~in~ with a HPC-content of 0.1 to 50 mg/g.

By using viscosity incl~iilg ~ $, it is possible to produce tenside-free SLN-.l;~

F , ~r 11:

10.0 g Ol~ ilaurate (Dynasan 112) 0.5 g tylose MH 300 89.5 g water for injection purposes The production was done as ~eccrihed in example 1. However, the high-pressure h O. nn was carried out at 500 x105 pa (500 bar) (three cycles). The PCS-diameter of the main poF~ nn was 879 nm with a poly~ ily index of 0.367.

By varying the p~ ;ng cnn~ innc it is possible to produce SLN-~with a mean Pcs~lismst~t below 100 nm.

~#

Example 12:

10.0 g o~ ' (Dynasan 112) 5.0 g lipoid S75 85.0 g water for injection purposes The production was done as descrihed under example 1. However, the high-pressure ~ ~O ~nn was carried out at 1500 x 105 pa (1550 bar) (three cycles).

The PCS-diameter of the main ~C-r ~ nn was 88 nm (obtained through polyJi~,. ,;ly analysis by means of Fourier's llal~ru~,,dlion of the obtained correlation function).

The invention also includes the p~UCeJulG to produce the described drug carrier as well as its use for ~ ' n3 active ' Seen on the whole, the solid lipid la ~ ~ combine the ad~,auLges of polymer ~opa~licles (solid core, controllable lil,~.- nn over a longer period of time, pnC-C-ibility of ill~.UllJUI ' 3 hydrophilic drug) with the advantages of pal~ I fatty em~ mc (1~ vt;ly fast d~ ' nn, low or no toxicity, p.~J~, :h;li~y on an ir~ ri~l scale by methods e~l -hli~l. A for the ~ products, no ~1iffrul~ c- with li nn by; -' ving) by avoiding the disadvantages of ~p~licles (too slow dFgr- ' in vivo or toxic dP.g~y~ 'nn products, lack of scaling-up poccihility in the ~I.h.~t ) and the ~ i g of fatty .9 ~1~: "-c (e.g. very quick I ' -li, -n, very fast liberation of the mPA;~in~

~B

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the manufacture of a drug carrier which comprises tenside-containing or tenside-free particles of lipid or lipid-like (lipoid) material, or mixture thereof, which have a diameter of 10 nm to 10 µm whereby the particles of the main population have an average diameter of between 40 and 1000 nm and are solid at room temperature characterized by the fact that either an inner phase of the lipid or lipid-like (lipoid) material is homogenized under high pressure in a dispersion medium (water aqueous solution or a liquid miscible with water) in a melted or softened state, or the inner phase is dispersed under high pressure in the dispersion medium in a solid state, whereby the solid phase is finely broken down.

2. Process as in claim 1, characterized by the fact that the particles of the main population have an average diameter of 100 to 500 nm.

3. Process according to claim 1 characterized by the fact that the particles of the main population have an average diameter of 40 to 80 nm.

4. Process as in one of claims 1 to 3 characterized by the fact that the proportion of the inner or lipid phase in relation to the basic preparation is 0.1 to 30% by weight.

5. Process according to one of claims 1 or 3 characterized by the fact that the proportion of the inner or lipid phase in relation to the basic preparation is 1 to 10% by weight.

6. Process as in one of claims 1 to 5 characterized by the fact that the lipid particle material comprises monoglyceride, diglyceride, triglyceride, fatty alcohols and the esters or ethers thereof, waxes and lipid peptides or mixtures of these.

7. Process as in one of claims 1 to 6 characterized by the fact that the triglyceride comprises glycerine trilaurate, glycerine myristate, glycerine palmitate, glycerine stearate and glycerine behenate, that the fatty alcohol comprises cetyl and stearyl alcohol and the wax comprises cetyl palmitate and bleached beeswax.

8. Process as in one of claims 1 to 7 characterized by the fact that, in addition, the drug carrier includes one or more dispersion-stabilizing substances, whereby the dispersion-stabilizing substances are included in a quantity of 0.1 to 20% by weight in relation to the basic preparation.

9. Process according to one of claims 1 to 7 characterized by the fact that, in addition, the drug carrier includes one or more dispersion stabilizing substances, whereby the dispersion stabilizing substances are included in a quantity of 0.5 to 5% by weight in relation to the basic preparation.

10. Process as in claim 8 or 9 characterized by the fact that the dispersion stabilizing substances comprise compounds from the series of poloxamers, poloxamins, ethoxylated monoglycerides and diglycerides, ethoxylated lipids and lipoids, ethoxylated fatty alcohols and alkyl phenois, ethoxylated fatty acid esters, polyglycerine ethers and esters, lecithins, esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols phospholipids and sphingolipids, sterois or the esters and ethers thereof, as well as mixtures of these compounds.

11. Process as in one of claims 8 to 10 characterized by the fact that the dispersion stabilizing substance comprises egg-lecithin, soya-lecithin or hydrogenated lecithin, mixtures thereof, or mixtures of one or both lecithins with one or more phospholipid components, cholesterin, cholesterin palmitate, stigmaterin or other sterols.

12. Process according to one of claims 1 to 11 characterized by the fact that, in addition, the drug carrier includes load stabilizers in a quantity of 0.01 to 10% by weight.

13. Process according to one of claims 1 to 11 characterized by the fact that in addition, the drug carrier includes load stabilizers in a quantity of 0.05 to 2% by weight.

14. Process as in claim 12 or 13 characterized by the fact that the charge-enhancing sterically stabilizing stabilizers comprises dicetyl phosphate, phosphatidylglycerol, saturated or unsaturated fatty acids, sodium cholate, sodium glycocholate, sodium taurocholate or mixtures thereof, antiflocculants or amino acids.

15. Process as in claim 8 or 9 characterized by the fact that the drug carrier comprises one or more viscosity-increasing substances, whereby the viscosity-increasing substances are included in a quantity of 0.1 to 10% by weight in relation to the basic preparation.

16. Process according to claim 8 or 9 characterized by the fact that the drug carrier comprises one or more viscosity-increasing substances, whereby the viscosity-increasing substances are included in a quantity of 0.5 to 5% by weight in relation to the basic preparation.

17. Process as in claim 15 or 16 characterized by the fact that the viscosity-increasing substances comprise cellulose ethers and esters, polyvinyl derivatives, alginates, polyacrylates, xanthanes and pectins.

18. Process as in one of claims 15 to 17 characterized by the fact that the drug carrier also comprises sugar or sugar alcohols, especially glucose, mannose, trehalose, mannitol and sorbitol.

19. Process as in one of the claims 15 to 18 characterized by the fact that the drug carrier also comprises load charged compounds.

20. Process as in one of claims 1 to 19 characterized by the fact that the particles are dispersed in distilled water, in an aqueous solution with additives of electrolytes, monosaccharides and disaccharides, polyols or mixtures thereof or a liquid that can be mixed with water, whereby the additives comprise, in particular, sodium chloride, mannose, glucose, fructose, xylose, trehalose, mannitol, sorbitol, xylitol and glycerol in a quantity of 0.1 to 50% by weight in relation to the basic preparation.

21. Process according to one of claims 1 to 19 characterized by the fact that the particles are dispered in distilled water in an aqueous solution with additives of electrolytes, monosaccharides and disaccharides, polyols or mixtures thereof or a liquid that can be mixed with water, whereby the additives comprise, in particular, sodium chloride, mannose, glucose, fructose, xylose, trehalose, mannitol, sorbitol, xylitol and glycerol in a quantity of 1 to 30%
by weight in relation to the basic preparation.

22. Process as in one of claims 1 to 21, characterized by the fact that the particles are lyophilised or spray-dried.

23. Process as in claim 1, characterized by the fact that the drug carrier is manufactured without the use of halogenated organic solvents.

24. Process as in one of claims 1 to 23, characterized by the fact that the drug carrier includes no active substance, or one or more active substances.

25. Process as in claim 24, characterized by the fact that the active substance or substances are dissolved or dispersed in the particles, absorbed on the surface of the particles or dispersed in the particles as an aqueous solution.

26. Process as in claim 24 characterized by the fact that the drug carrier contains one or more active substances and is suitable for intravenous administration, intramuscular administration, intra-arthricular administration, intracavital administration, subcutaneous administration, intradermal administration, enteral administration, pulmonary application and topical and ophthalmological application.

27. A drug carrier consisting of tenside-free particles of lipid or lipid-like (lipoid) material, or mixtures thereof, with a diameter of 10 nm to 10 nu which are manufactured by means of a high-pressure homogenization process in accordance with one of the claims 1 to 26 whereby the particles of the main population have an average diameter of between 40 and 1000 nm and are solid at room temperature.

28. A drug carrier according to claim 27, characterized by the fact that the particles of the main population have an average diameter of 100 to 500 nm.

29. A drug carrier according to claim 27, characterized by the fact that the particles of the main population have an average diameter of 40 to 80 nm.

30. A drug carrier according to one of claims 27 to 29, characterized by the fact that the proportion of the inner or lipid phase in relation to the basic preparation is 0.1 to 30% by weight.

31. A drug carrier according to one of claims 27 to 29, characterized by the fact that the proportion of the inner or lipid phase in relation to the basic preparation is 1 to 10% by weight.

32. A drug carrier according to one of claims 27 to 31 characterized by the fact that the particle material comprises monoglyceride, diglyceride, triglyceride, fatty alcohols and the esters or ethers thereof, waxes and lipid peptides or mixtures of these.

33. A drug carrier according to any one of claims 27 to 32 characterized by the fact that the triglyceride comprises glycerine trilaurate, glycerine myristate, glycerine palmitate, glycerine stearate and glycerine behenate, that the fatty alcohol comprises cetyl and stearyl alcohol and the wax comprises cetyl palmitate and bleached beeswax.

34. A drug carrier according to one of claims 27 to 33 characterized by the fact that in addition, the drug carrier includes one or more dispersion stabilizing substances, whereby the dispersion stabilizing substances are included in a quantity of 0.1 to 20% by weight in relation to the basic preparation.

35. A drug carrier according to any one of claims 1 to 33 characterized by the fact that in addition the drug carrier includes one or more dispersion stabilizing substances, whereby the dispersion stabilizing substances are included in a quantity of 0.5 to 5% by weight in relation to the basic preparation.

36. A drug carrier according to claim 34 or 35 characterized by the fact that the dispersion stabilizing substances comprise compounds from the series of poloxamers, poloxamins, ethoxylated monoglycerides and diglycerides, ethoxylated lipids and lipoids, ethoxylated fatty alcohols and alkyl phenois, ethoxylated fatty acid esters, polyglycerine ethers and esters, lecithins, esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols phospholipids and sphingolipids, sterois or the esters and ethers thereof, as well as mixtures of these compounds.

37. A drug carrier according to one of claims 34 to 36 characterized by the fact that the dispersion stabilizing substance comprises egg-lecithin, soya-lecithin or hydrogenated lecithin, mixtures thereof, or mixtures of one or both lecithins with one or more phospholipid components, cholesterin, cholesterin palmitate, stigmaterin or other sterols.

38. A drug carrier according to any one of claims 27 to 37 characterized by the fact that in addition the drug carrier includes charge enhancing sterically stabilizing stabilizers in a quantity of 0.01 to 10% by weight.

39. A drug carrier according to any one claims to 27 to 37 characterized by the fact that in addition the drug carrier includes charge enhancing sterically stabilizing stabilizers in a quantity of 0.05 to 2% by weight.

40. A drug carrier according to claim 38 or 39 characterized by the fact that the charge-enhancing sterically stabilizing stabilizers comprise dicetyl phosphate, phosphatidylglycerol, saturated or unsaturated fatty acids, sodium cholate, sodium glycocholate, sodium taurocholate or mixtures thereof, antiflocculants or amino acids.

41. A drug carrier according to claim 34 or 35 characterized by the fact that the drug carrier comprises one or more viscosity increasing substances, whereby the viscosity increasing substances are included in a quantity of 0.1 to 10% by weight in relation to the basic preparation.

42. A drug carrier according to claim 34 or 35 characterized by the fact that the drug carrier comprises one or more viscosity increasing substances, whereby the viscosity increasing substances are included in a quantity of 0.5 to 5% by weight in relation to the basic preparation.

43. A drug carrier according to claim 41 or 42 characterized by the fact that the viscosity increasing substances comprise cellulose ethers and esters, polyvinyl derivatives, alginates, polyacrylates, xanthanes and pectins.

44. A drug carrier according to one of claims 41 to 43 characterized by the fact that the drug carrier also comprises sugar or sugar alcohol, especially glucose, mannose, trehalose, mannitol and sorbitol.

45. A drug carrier according to one of claims 41 to 44 characterized by the fact that the drug carrier also comprises load charged compounds.

46. A drug carrier according to one of claims 27 to 45 characterized by the fact that the particles are dispersed in distilled water, in an aqueous solution with additives of electrolytes, monosaccharides and disaccharides, polyols or mixtures thereof or a liquid that can be mixed with water, whereby the additives comprise, in particular, sodium chloride, mannose, glucose, fructose, xylose, trehalose, mannitol, sorbitol, xylitol and glycerol in a quantity of 0.1 to 50% by weight in relation to the basic preparation.

47. A drug carrier according to one of claims 27 to 45 characterized by the fact that the particles are dispersed in distilled water, in an aqueous solution with additives of electrolytes, monosaccharides and disaccharides, polyols or mixtures thereof or a liquid that can be mixed with water, whereby the additives comprise, in particular, sodium chloride, mannose, glucose, fructose, xylose, trehalose, mannitol, sorbitol, xylitol and glycerol in a quantity of 1 to 30% by weight in relation to the basic preparation.

48. A drug carrier according to one of claims 27 to 47 characterized by the fact that the particles are lyophilised or spray-dried.

49. A drug carrier as in claim 27 characterized by the fact that the drug carrier is manufactured without the use of halogenated organic solvents.

50. A drug carrier according to one of claims 27 to 49 characterized by the fact that the drug carrier includes no active substance, or one or more active substances.

51. A drug carrier according to claim 50 characterized by the fact that the active substance or substances are dissolved or dispersed in the particles, absorbed on the surface of the particles or dispersed in the particles as an aqueous solution.

52. A drug carrier according to claim 50 characterized by the fact that the drug carrier contains one or more active substances and is suitable for intravenous administration, intramuscular administration, intra-arthricular administration, intracavital administration, subcutaneous administration, intradermal administration, enteral administration, pulmonary application and topical and ophthalmological application.

53. Use of a drug carrier as in one of claims 27 to 52 for the manufacture of drugs which are in particular suitable for intravenous administration, intramuscular administration, intra-arthricular administration, intracavital administration, subcutaneous administration, intradermal administration, enteral administration, pulmonary application and topical and ophthalmological application.