EP1476137A1 - Composition comprising low water soluble compounds within porous carriers - Google Patents

Composition comprising low water soluble compounds within porous carriers

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Publication number
EP1476137A1
EP1476137A1 EP03734705A EP03734705A EP1476137A1 EP 1476137 A1 EP1476137 A1 EP 1476137A1 EP 03734705 A EP03734705 A EP 03734705A EP 03734705 A EP03734705 A EP 03734705A EP 1476137 A1 EP1476137 A1 EP 1476137A1
Authority
EP
European Patent Office
Prior art keywords
low water
active compound
support material
membrane
biologicauy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP03734705A
Other languages
German (de)
French (fr)
Inventor
Steve PHARES Drug Delivery AG LEIGH
Mathew Louis Steven Leigh
Peter Van Hoogevest
Henricus Tiemessen
Jacques Quinton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Phares Pharmaceutical Research NV
Original Assignee
Phares Pharmaceutical Research NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Phares Pharmaceutical Research NV filed Critical Phares Pharmaceutical Research NV
Priority to EP03734705A priority Critical patent/EP1476137A1/en
Publication of EP1476137A1 publication Critical patent/EP1476137A1/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds

Definitions

  • the present invention relates to compositions for improving the solubility or dispersibility of biologically active compounds having low water solubility in molecular association or in ultra fine form.
  • a specific object of the invention is to improve the dissolution rate or dispersive properties of a lipophilic compound with low water solubility and its bioavailability, without using energy intensive methods for particle size reduction or relying on the presence of high levels of solvents in the composition.
  • a major benefit of the present invention is that extensive milling procedures, such as wet-milling to obtain sub-micron drug particles are avoided.
  • the lipophilic compound is in ultra fine form with large surface areas with improved dispersibility and increased dissolution profile compared to micronised drug particles.
  • the biologically active compound with low water solubility is held inside the pores of a suitable support material in association or solution in a suitable membrane lipid and/ or surfactant or is present as ultrathin layer(s) and/ or ultrafine amorphous particles with or without lipid and/ or surfactant.
  • the compositions may be further processed into suitable dosage forms, such as semi-solid and solid dosage forms, with minimum effort.
  • Improvement of dispersibility and dissolution rates employ size reduction methods for obtaining small particles of water insoluble compounds, and/ or require fillers, diluents, anti- caking and adsorptive aids to stabilise the external surfaces of micronised drug particles to prevent agglomeration.
  • energy mills are used to micronise active materials with the aim of improving solubility from the large external surface areas created. Preventing clumping and crystal growth of micronised or precipitated particles is a problem and in reality the methods often fail to produce significant increases in bioavailability.
  • US-A-5,091,188 discloses injectable compositions in which insoluble or poorly soluble drugs in powder form are stabilized against agglomeration during storage by treating the external surface of the particles with one or more layers of phospholipid.
  • WO 99/49846 discloses compositions and procedures that yield sub-micron and micron size stable crystalline particles of water-insoluble drugs.
  • the surfaces are treated with phospholipid, a charged surface modifier and a block copolymer.
  • high shear mixing with multiple passes through a micro fluidiser is necessary to produce particles of sufficiently small size.
  • WO 99/65469 further discloses submicron particles of water-insoluble drugs, prepared simultaneously by stabilising microparticulate suspensions of the drug with surface modifier molecules e.g. a phospholipid, by rapid expansion into an aqueous medium from a compressed solution of the compound and surface modifiers in a liquified gas.
  • the particles of the drug are surface stabilised in the suspension in order to prevent agglomeration.
  • EP-A-0 795 585 discloses a process for preparing finely divided particulate suspensions of a retinoid or carotenoid in a volatile, organic solvent mixed with aqueous medium in the presence of a physiologically compatible emulsifying agent, e.g. lecithin.
  • the prior art also describes methods of preparing co-precipitates with or without lipids with the aim of improving solubility.
  • preparation of lipid-drug co-precipitates using diacyl phospholipids to increase the dissolution behaviour of poorly water soluble drug solvates, and the possibility of modifying drug release from such dispersions by incorporating small amounts( ⁇ 0.05%) of poly vinyl pyrrolidone is described in J. Pharm. Sci. 81, 283-286 (1992).
  • the compositions are prepared essentially by co-precipitation which results in the incorporation of lipid in the crystalline structure of the solvate. The residual solvent trapped in the solvate crystals is given as a possible reason for the improved solubility of the poorly water soluble compound.
  • PCT/US86/00637 discloses the use of non-esterified fatty acids and monoglycerides together with minor amounts of a monoacyl lipid (lysophosphatidylcholine) to form lipid particles which show improved oral absorption for various lipophilic compounds. Improved oral absorption is claimed to be due to the unique properties of the mixture.
  • WO 98/58629 describes lipid compositions comprising at least one monoacyl lipid, e.g. monoacyl phospholipid and mixtures of monoacyl and diacyl phospholipids that are effective in carrying lipophilic compounds in molecular form.
  • the compositions may be a waxy solid, a paste-like material or a viscous fluid suitable for filling into hard or soft gelatin capsules.
  • WO 00/38655 describes a dosage form comprising a plurality of particles having interior pores and a liquid, active agent formulation in the pores to retain substantially all of the liquid active agent formulations in the pores during compaction.
  • the method explicitly requires the liquid to remain inside the pores dissolved in a non volatile liquid such as propylene glycol.
  • the procedure used is for absorbing liquids described in the NeusilinTM brochure (Fuji Chemical).
  • WO 00/38655 is concerned with powder compositions containing absorbed liquid solutions/ suspensions and a method to modify the dissolution characteristics of both hydrophilic and lipophilic compounds.
  • US 20010009677 discloses a solid oral dosage form comprising a solid carrier of magnesium alumina silicate, an effective amount of a lipophilic stanol ester and a mixed micelle surfactant system to solubilise the compound using a hot melt method, which coats and deposit the compound on the external surfaces of the core particles. It is silent with respect to the lipophilic compound being sequestered and maintained in ultra fine form or in molecular solution inside the pores of the carrier. Furthermore, the compositions do not comprise membrane lipids or a method of introducing the compound into the pores of a support medium by means of a solvent with or without membrane lipid and/ or surfactants, followed by removal of the solvent.
  • US-A-5,624,687 discloses a soluble salt of compounds with low water solubility at elevated pH dissolved in an organic solvent mixture containing an enteric base coated onto core particles like magnesium alumina silicate to make a solid quick-dissolution preparation with increased oral bioavailability. It is claimed that the compound is deposited as a solid solution in an enteric base on the exterior surfaces of the core particles from sprayed droplets.
  • the core particles include calcium hydrogen phosphate, sucrose, lactose, starch and crystalline cellulose. It does not disclose the sequestration of drugs which have low water solubility at neutral pH in the internal pores of a porous support medium in ultra fine or molecular form with or without membrane lipids and/ or surfactants.
  • the solid dispersion carrier is a surfactant which solubilises the drug without using a solvent and the increase in dissolution was attributed to the formation of a solid solution on the surface of the particles.
  • the method does not involve a solvent to reach the internal pores of the carrier, from where it is removed.
  • Subject matter of the present invention is a composition, particularly a pharmaceutical or cosmetic composition, for improving the dispersibility of biologically active compounds having low water solubility regardless of pH which comprises, a) A biologically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; c) A membrane lipid; or, in the alternative, a membrane lipid combined with a pharmaceutically acceptable surfactant; and, optionally, d) Additional pharmaceutically acceptable excipients.
  • “Compounds” are biologically active substances that have a physiological and/ or pharmacological effect. They are also referred to as drugs or therapeutic agents and include nutrition agents, food and feed additives, cosmetic and diagnostic substances. "Low water solubility” means any compound that requires more than 10 parts of water to dissolve 1 part of the compound. It spans the definitions between sparingly soluble (from 10 to 30) to very slightly soluble (from 1000 to 10 000) and practically insoluble or insoluble (10 000 and over) as defined in USP 24. The term includes hydrophobic or lipophilic or amphipathic compounds. “Lipid” refers to membrane lipids, which include phospholipids, glycolipids, ceramides, gangliosides and cerebrosides. The term as used herein refers to a single type as well as to mixtures thereof.
  • Lipid suspension refers to an aqueous dispersion of lipid particles.
  • Silicone material refers to highly porous clusters or agglomerates of small particles held together by physical forces creating large internal surfaces in the inter-particulate pores or channels which are accessible to solvents.
  • Ultra fine form implies that the compound is in the finest state of subdivision possibly as amorphous particles or ultrathin layer but not in molecular dispersion or solution in the pores, or after hydration and contact of the composition with aqueous media.
  • Adsorption refers to the containment or sequestering of a compound on the external as well as internal surfaces lining the pores of the support material.
  • “adsorption” refers to the containment, impregnation or sequestering of a compound “essentially” (more than 90%, particularly 95%) on the external as well as internal surfaces lining the pores of the support material.
  • "Ultrafine dispersion” is achieved if more than 50% of the drug is able to pass a 0.45 micron filter after incubation of the composition in a suitable dissolution medium, such as 0.5% SDS (sodium dodecyl sulphate) in 0.1N HC1 or another dissolution media used for dissolution testing.
  • composition according to the present invention has improved dispersibility and dissolution profiles and may be used as such, or preferably converted to free flowing powders or granules with excipients such as sugars and polymers which increase the bulk density.
  • the composition may also be processed further by known methods, such as extrusion, and compacted into tablets or filled into hard gelatine capsules or the like by addition of suitable additional excipients commonly used in solid dosage forms.
  • Organic and inorganic materials widely used as anti-caking agents, disintegrants, fillers, adsorbents, pulverising or moulding excipients may be used.
  • the composition may be suspended in a liquid vehicle for topical applications.
  • the support material dissolves at least partially in the low pH conditions of the upper Gl-tract to release the compound in ultra fine form or in molecular dispersion.
  • the key function of the support material is to enable a compound with low water solubility to be deposited inside the pores in highly dispersive ultrafine form.
  • the prior art only describes the use of solid particulate carriers either to absorb liquids to facilitate handling and storage or as diluents and core materials coated on the external surfaces of the particles by a solid compound.
  • dissolution takes place inside the body after oral ad- ministration. It is believed that the support material impregnated with lipophilic substance with or without surfactant and/ or lipid readily disperses and/ or dissolves in the GI- tract, releasing the lipophilic compound from the pores. This improves the dissolution profile of a compound with low water solubility.
  • a powder composition comprising the compound sequestered in ultra fine form inside a support material may be further treated with acid medium in a suitable container.
  • the support material is dissolved and the lipophilic compound may be harvested or collected as ultra fine powder.
  • the powder has improved dispersibility and dissolution profiles and may be processed further into suitable dosage forms.
  • An alternative and preferred embodiment of the invention relates to a pharmaceutical or cosmetic composition for improving the dispersibility of biologically active compounds having low water solubility, which comprises a) A therapeutically or cosmetically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; c) At least one membrane lipid; and, optionally, d) Additional pharmaceutically acceptable excipients.
  • Another alternative embodiment of the invention relates to a pharmaceutical or cosmetic composition for improving the dispersibility of biologically active compounds having low water solubility, which comprises a) A therapeutically or cosmetically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; c) At least one membrane lipid combined with at least one pharmaceutically acceptable surfactant; and, optionally, d) Additional pharmaceutically acceptable excipients.
  • An example of the invention relates to a pharmaceutical composition for improving the dispersibility of a HIV-protease inhibitor, particularly a HIV-1-protease inhibitor of low water solubility, which comprises a) A therapeutically effective amount of a HIV protease inhibitor; b) A porous particulate support material capable of incorporating within its pores the biologically active compound, and optionally; c) At least one membrane lipid and/ or at least one a pharmaceutically acceptable surfactant; and, optionally, d) Additional pharmaceutically acceptable excipients.
  • Another selective and preferred embodiment of the invention relates to a pharmaceutical composition for improving the dispersibility of cyclosporins, particularly cyclosporin A or G, which comprises a) A therapeutically effective amount of cyclosporin A; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; and, optionally; c) A pharmaceutically acceptable surfactant; or, in the alternative, a pharmaceutically acceptable surfactant combined with a membrane lipid; and, optionally, d) Additional pharmaceutically acceptable excipients.
  • a further embodiment of the invention relates to a pharmaceutical composition for improving the dispersibility of peripheral benzodiazepine receptor ligand with activity in neuro-degenerative diseases which comprises: . . J . .
  • compositions comprising a porous support material and organic solutions/ aqueous suspensions containing a drug and a surfactant and/ or a membrane lipid as a minor component(s) as compared to the amount of the support material, and which yields after hydration and/ or dissolution of the carrier (dosage form) in-vivo or in-vitro, ultra fine drug particles associated with surfactant or a mixture of surfactant and lipids, possibly in the amorphous state; or
  • the invention relates to a process for the preparation of a pharmaceutical or cosmetic dosage form, as defined above, which is characterised in that in a suitable solvent or solvent mixture a homogeneous dispersion is prepared, which comprises, a) A biologically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; and, optionally, c) A membrane phospholipid; and/ or a pharmaceutically acceptable surfactant; d) Additional pharmaceutically acceptable excipients.
  • Component d) may be added during loading and impregnation of the compound with low water solubility using a solvent or solvent mixture, followed by drying or solvent removal. Component d) may be added during or after loading and impregnation of the compound. The homogeneous dispersion is converted to a dosage form suitable for pharmaceutical or cosmetic administration.
  • the process comprises the following inventive process embodiments, wherein the component a), biologically active compound having low water solubility is present in combination with the component b), the porous particulate support material, the presence of components a) and b) combined with
  • a membrane lipid as defined below, or
  • a pharmaceutically or cosmetically acceptable surfactant as defined above; is optional.
  • the presence of additional pharmaceutically or cosmetically acceptable excipients, component d), is optional in any of the embodiments described above.
  • a further embodiment of the invention relates to a method for improving the dispersibility of biologically active compounds having low water solubility, which comprises i) Dissolving or dispersing a biologically effective amount of at least one biologically active compound having low water solubility in a suitable volatile pharmaceutically acceptable solvent; ii) Dissolving or dispersing in the compound solution at least one membrane phospholipid; or, in the alternative, at least one pharmaceutically acceptable surfactant; or mixture of said membrane lipid and surfactant, optionally, additional pharmaceutically acceptable excipients; and iii) Adding the solution to a porous particulate support material capable of incorporating within its pores the biologically active compound; followed by removal of the solvent, to produce a composition with increased aqueous dispersibility of said compound.
  • An alternative method relates to a method for improving the dispersibility of biologically active compounds having low water solubility, which comprises j) Dissolving or dispersing a biologically effective amount of at least one biologically active compound having low water solubility in a suitable volatile pharmaceutically acceptable solvent; ii) Adding the solution or dispersion to a porous particulate support material capable of incorporating within its pores the biologically active compound; followed by removal of the solvent, to produce a composition with increased aqueous dispersibility of said compound and optionally other excipients.
  • Another embodiment of the invention relates to a specific method for preparing said dosage forms, which includes the following process steps: i) dissolving or dispersing drug in a solvent or solvent water mixture or aqueous medium containing, optionally at least one membrane lipid and/ or pharmaceutically acceptable surfactant. ii) adding the suspension or solution to a porous support material; iii) optionally followed by removal of said water or solvent.
  • the present invention relates particularly to processes and methods for providing:
  • a composition for improving the dispersibility, dissolution and the bioavailability of a biologically active compound having low water solubility comprising, a) A therapeutic amount of a biologically active compound having low water solubility; b) A particulate porous support material capable of sequestering the biologically active compound within its pores; c) At least one membrane lipid or a mixture of membrane lipid and surfactant and, optionally, d) Other pharmaceutically acceptable excipients.
  • composition for improving the dispersibility, dissolution and the bioavailability of a biologically active compound having low water solubility comprising, a) A therapeutic amount of a biologically active compound having low water solubility; b) A particulate porous support material capable of sequestering the biologically active compound within its pores; optionally c) At least one membrane lipid and/ or a mixture of membrane lipid and surfactant ; d) Other pharmaceutically acceptable excipients.
  • a composition for improving the dispersibility, dissolution and the bioavailability of a biologically active compound having low water solubility comprising, a) A therapeutic amount of a biologically active compound having low water solubility; b) A particulate porous support material capable of sequestering the biologically active compound within its pores; c) At least one surfactant, and optionally at least one membrane lipid and, optionally, d) Other pharmaceutically acceptable excipients.
  • compositions, in which the surf actant is selected from the group consisting of d- ⁇ -tocopheryl polyethylene glycol 1000 succinate, a poloxamer, polyethoxylated castor oil derivative and a protective colloid
  • compositions wherein the weight ratio of the surfactant to active compound with low water solubility, or preferably, surfactant or surfactant lipid mixture to support material is less or equal to 1 : 2 by weight
  • a dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before and comprising a therapeutic amount of a biologically active compound having low water solubility • A dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before and comprising a therapeutic amount of a biologically active compound having low water solubility and in which the support material is amorphous aluminometasilicate or calcium silicate in particulate form • A dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before comprising a therapeutic amount of a biologically active compound having low water solubility; and in which the support material is amorphous Al 2 O 3 -MgO-1.7 SiO-7H 2 O or Ca 2 SiO 4 or CasSiOs or a mixture of Ca 2 SiO 4 and Ca 3 SiOs in particulate form
  • a dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before comprising a therapeutic amount of a biologically active compound having low water solubility and in which the support material is dibasic anhydrous calcium phosphate
  • a dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before comprising a therapeutic amount of a biologically active compound having low water solubility, which after (partial) dissolution of the porous support in 0.1 M HCL containing 0.5% sodium dodecylsulphate results in a molecular association or solution of the biologically active compound having low water solubility in the membrane lipid
  • a method for the preparation of a composition for improving the dissolution and the bioavailability of a biologically active compound having low water solubility wherein, A biologically active compound having low water solubility and surfactant and optionally a lipid are first finely dispersed or preferably dissolved in a suitable solvent,
  • the solution or suspension is mixed with a porous support material, followed by drying or solvent removal preferably by means of reduced pressure or vacuum to ensure maximum adsorption and sequestering of the compound in the pores; optionally the support material is dissolved, yielding a solution or an ultra fine suspension of the compound, preferably in association with the lipid; optionally the solution of ultra fine suspension is further processed to obtain a free flowing powder by evaporating the solvent •
  • a method for the preparation of a composition for improving the dissolution and the bioavailability of a biologically active compound having low water solubility wherein,
  • a biologically active compound having low water solubility and optionally surfactant and/ or a lipid is first finely dispersed or preferably dissolved in a suitable solvent,
  • the solution or suspension is mixed with a porous support material, followed by drying or solvent removal preferably by means of reduced pressure or vacuum to ensure maximum adsorption and sequestering of the compound in the pores; optionally the support material is dissolved, yielding a solution or an ultra fine suspension of the compound, preferably in association with the lipid; optionally the solution of ultra fine suspension is further processed to obtain a free flowing powder by evaporating the solvent
  • a therapeutic amount of a biologically active compound having low water solubility and surfactant and optionally a lipid are first finely dispersed or preferably dissolved in a suitable solvent;
  • the solution or dispersion is loaded into the pores of a porous support material, preferably by means of reduced pressure or vacuum to ensure maximum adsorption and sequestering of the compound in the pores;
  • the support material is dissolved, yielding a solution or an ultra fine suspension of the compound, preferably in association with the lipid;
  • composition is further processed by extrusion into granules e.g. for filling in hard gelatine capsules, and/ or compacted into tablets by addition of suitable excipients commonly used in solid dosage forms, such as, for example as anti-caking agents, disintegrants, fillers, adsorptives, pulverizing and moulding excipients.
  • suitable excipients commonly used in solid dosage forms, such as, for example as anti-caking agents, disintegrants, fillers, adsorptives, pulverizing and moulding excipients.
  • a biologically active compound having low water solubility is, in particular, any therapeutic agent or a combination of different therapeutic agents of low water solubility, which is suitable in a therapeutically effective amount for the intended mode of administration, e.g. topi- cal, parenteral, e.g. intramuscular in the form of injection dispersions, or oral, e.g. in the form of capsule fillings.
  • a preferred therapeutic agent is sparingly soluble in water and has a solubility in water of less than 500 mg/1000 ml, especially of less than 100 mg/1000 ml.
  • Suitable for topical, parenteral, e.g. intramuscular, or oral administration, e.g. as capsule fillings are sparingly soluble therapeutic agents, e.g.
  • immunosuppressants having a macrolide structure, typically cyclosporin A, cyclosporin G, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, gusperimus, non-steroidal antiphlogistic agents and salts thereof, typically acetylsalicylic acid, ibuprofen or S(+)-ibuprofen, indomethacin, diclofenac (Na and K-salt), piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen, fenoprofen, felbinac, sulindac, etodolac, oxyphenbutazone, phenylbutazone, nabumetone; dihydro- pyridine derivatives having cardiovascular activity, e.g.
  • the above-mentioned therapeutic agent may be present in the pharmaceutical composition in the form of a pharmaceutically acceptable salt, typically as hydrobromide, hydrochloride, mesylate, acetate, succinate, lac- tate, tartrate, fumarate, sulphate, maleate, and the like.
  • a pharmaceutically acceptable salt typically as hydrobromide, hydrochloride, mesylate, acetate, succinate, lac- tate, tartrate, fumarate, sulphate, maleate, and the like.
  • corticoids for dermal administration e.g. halogenated corticoids, e.g.
  • corticoids e
  • corticoids may also be combined with antimycotic, sulphonamides or estrogen derivatives.
  • Suitable for dermal formulations are also astringents, anti-acne agents, antipsoriasis agents, or antipruritic agents.
  • Particularly suitable for topical administration are topical antibiotics, e.g.
  • tetracyclin erythromycin, fusidinic acid, framycetine sulphate, neomycin, meclocyclin, gentamycin, leu- comycin, streptomycin, ganefromycin, rifamexil, ramoplanin, spiramycin, clindamycin, ba- citracin, oxytetracyclin, sulphonamides, and other antibacterial and antiviral agents, e.g. po- dophyllotoxin, idoxuridin, heparine, foscarnet, vidarabine, tromantadine, idoxuridine, aci- clovir, antimycotic agents, e.g.
  • antibiotics and antimycotic agents may be combined with other corti- costeroids, antibiotics or antimycotic agents.
  • sunscreens for topical administration are active agents such as UV-B filtering substances, e.g. 4-aminobenzoic acid, homosalate, oxybenzon, 3-imidazolyl-4-yl-acrylic acid and derivatives thereof, 2-phenylbenzimidazol-5-sulphonic acid and salts thereof; 2,3- dihydroxypropyl-4-amino-benzoate, 2-ethylhexyl-4-dimethyl-aminobenzoate, ethyl 4-[bis(2- hydroxypropyl)amino]benzoate, 2-ethylhexyl-4-methoxy-cinnamate, 2-ethylhexylsalicylate, ethylpoly(oxyethylene)-4- ⁇ bis-[(2-hydroxyethyl)-polyoxyethylene]amino ⁇ benzoate, 3-(4- imidazolyl) acrylic acid, isopentyl 4-methoxycinnamate, 4-isopropylbenzoic
  • Particularly suitable for topical administration are also lipophilic vitamins, typically vitamin A (retinol, free acid or derivatives thereof), B (Bl: thiamine, B2: riboflavine, B6: pyrid- oxin, panthenol, pantothenic acid, vitamin B12 and combinations thereof), vitamin C, D, E (tocopherol), biotin or vitamin K; membrane hpids with functional properties, also retinoids and carotinoids, oils with therapeutic, antimicrobial, cosmetic organoleptic properties, such as cumin seed oil, wheat germ oil, shea butter, sebum regulators and sterols, pumpkin oil, borage and evening primrose oils.
  • the concentration of the therapeutic agent or combination thereof is determined by the known dosage amount to be administered and can be in the range from 1.0 to 30.0% by weight, preferably from 5.0 to 20.0% by weight, more particularly from 5.0 to 12.0% by weight, based on the weight of the carrier composition.
  • Suitable lipophilic feed additives are astaxanthin, canthaxanthin, zeaxanthin and lutein.
  • compounds used in nutriceuticals are ubiquinones, sitostanols, sitosterols and antioxidants such as lycopenes, B-carotene, polyphenols, isoflavones.
  • lipophilic drugs are immunosuppressants e.g. cyclosporin A, cytostatics e.g. taxol, anti inflammatories e.g. ibuprofen, HIV proteases, antinypertensives e.g. nifedipine, felodipine, photosensitisers e.g. benzoporphyrin, zinc phthalocyanine tin-ethyl purpurine and antibiotics e.g. amphotericin, ny statin, chloramphenicol.
  • immunosuppressants e.g. cyclosporin A
  • cytostatics e.g. taxol
  • anti inflammatories e.g. ibuprofen
  • HIV proteases HIV proteases
  • antinypertensives e.g. nifedipine, felodipine
  • photosensitisers e.g. benzoporphyrin
  • the support material is selected such that it does not chemically react with the active compound and serves little physiological role other than to maintain and stabilise a hydrophobic compound in dispersion.
  • the primary particles making up the agglomerates are smaller than 1 ⁇ and may be as small as about 0.02 ⁇ . These are held together by physical forces.
  • the size of the agglomerates is in the range between about 2 ⁇ to about 250 ⁇ , with inter-particle channels or pores accounting for specific surface areas between 50m 2 / g to 500 m 2 /g. Because of the very large internal surfaces available for adsorption, the support material is porous and highly absorbent.
  • the invention comprises as component b) a porous particulate support material selected from the group consisting of, for example, amorphous aluminometasilicate, calciumsilicate, silica, including porous silicon dioxide and silicic acid, dibasic anhydrous calcium phosphate and maltodextrin and polystyrene beads/ micro- sponges.
  • a porous particulate support material selected from the group consisting of, for example, amorphous aluminometasilicate, calciumsilicate, silica, including porous silicon dioxide and silicic acid, dibasic anhydrous calcium phosphate and maltodextrin and polystyrene beads/ micro- sponges.
  • Preferred support materials which are employed in this invention include inorganic solids, e.g. calcium hydrogen phosphate, which is corresponds to the general formula CaHP ⁇ 4*mH 2 O (m: 0 D m D2), particularly support materials commercially available of the type Fujicalin®, and magnesium aluminometasilicate, which corresponds to the general formula Al 2 O 3 , MgO , 2 Si0 2 , n H 2 O (n: 0 C3 n D2), particularly support materials commercially available of the type Neusilin®, calcium silicate, e.g. Ca2SiO4 or Ca3SiO, and dibasic anhydrous calcium phosphate.
  • inorganic solids e.g. calcium hydrogen phosphate, which is corresponds to the general formula CaHP ⁇ 4*mH 2 O (m: 0 D m D2)
  • support materials commercially available of the type Fujicalin®
  • magnesium aluminometasilicate which corresponds to the general formula Al 2 O
  • the composition comprises as component b) a porous particulate support material selected from the group consisting of amorphous Al 2 0 3 « MgO-2SiO 2 « nH 2 0, CaHPO 4 » mH 2 O, CaSiO 4 , CasSiOs and dibasic anhydrous calcium phosphate.
  • Suitable FUJICALIN products are SG and S and characterised by a mean pore size of 7,0 x 10- 10 m, a mean particle size of about 2-10 ⁇ , a specific volume of about 1.5 ml/g or more, a BET specific surface area of 20 m 2 /g to 60 m 2 /g, and an oil and water absorption capacity of about 0.7 ml/g.
  • Suitable NEUSILIN products are Grades SI, SGI, UFL2, US2, FH2, FLl, FL2,S2, SG2,NFL2N and NS2N. Particularly preferred grades are S , SGI US2 and UFL2. The most preferred support material for many applications is grade US2.
  • Those materials which are amorphous, typically have a specific area of about 100 m 2 /g to about 300 m 2 /g, an oil absorption capacity of about 1.3 ml/g to about 3.4 ml/g, a mean particle size of about 1 ⁇ to about 2 ⁇ and a spe- cif ic volume of about 2.1 ml/ g to about 12 ml/ g.
  • Suitable support materials are precipitated amorphous calcium silicate, e.g. Zeo- pharm® 600 with 300 m 2 /g, and oil absorption capacity of at least 450 ml/ 100 g, Hubersorb® 250 NF with oil absorbing capacity of 250 - 300 ml/ 100 g and Zeopharm® 80 (precipitated amorphous silica) with 140 m 2 /g and oil absorption capacity of 185 - 215 ml/ 100 g.
  • amorphous calcium silicate e.g. Zeo- pharm® 600 with 300 m 2 /g, and oil absorption capacity of at least 450 ml/ 100 g
  • Hubersorb® 250 NF with oil absorbing capacity of 250 - 300 ml/ 100 g
  • Zeopharm® 80 precipitated amorphous silica
  • amorphous support material typically have a specific area of about 100 m 2 /g to about 300 m 2 /g, an oil absorption capacity of about 1.3 ml/g to about 4.5 ml/g, a mean particle size of from about 1 ⁇ to about 2 - 14 ⁇ and a specific volume of about 2.1 ml/g to about 12 ml/g.
  • Another organic support material is maltodextrin supplied by Matsutani Chemical industry Co., Ltd. Japan (PineflowTM PineflowTM S) which has a specific surface area of 0.36 m 2 /g. 0.44 m 2 / g and oils absorbable capacity of 120 and 160%, respectively.
  • Alternative organic or inorganic porous materials may be used, as long as they have no deleterious effect on the active compound and present internal surface areas, which are comparably large.
  • the amount of support material depends on the surface area required for sequestering a solution or dispersion of the hydrophobic compound inside the pores and the type of solution employed. Generally, if the surface area provided by the particle agglomerates is in the range of 100 m 2 /g to 500 m 2 /g, about 2 g to about 10 g of the support material may be needed for every ml of liquid. However this is only a general guide and the ratio of the two components depends very much on the properties of the compound and processing conditions.
  • a suitable membrane lipid from synthetic or natural origin is selected from the group consisting of phospholipids, sphingolipids and glycolipids and mixtures thereof.
  • Membrane lipids are components of living cells. Suitable membrane lipids are phospholipids, which are the most abundant membrane lipid occurring in nature. They can be uncharged, zwitterionic, negatively or positively charged. Examples of uncharged phospholipids are phosphatidyl choline, phosphatidyl ethanolamine or their mono acyl derivatives, sphingomyelin and cholesterol. Examples of negatively charged membrane lipids are phosphatidyl serrne, phosphatidyl glycerol, phosphatidic acid, phosphatidyl inositol, cerebrocides, glycolipids cardiolipin.
  • the membrane lipids may be derived from natural plant or animal or microbiological sources, synthesised or partially synthesised, including polyethylene glycol (PEG) derived diacyl and monoacyl equivalents. Special fractions of soy lecithins which contain several phosholipid types, their monoacyl- derivatives, non polar lipids and free fatty acids have improved solubilisation potential and low viscosity due to their heterogeneous composition and may be preferred in some cases. Such blends are commercially available, for example, from Lipoid KG.
  • the term membrane lipid of natural origin also comprises membrane Hpids that have been modified by enzymatic action from natural sources.
  • the membrane phospholipid of component c) is selected from the group of diacylphosphatidylcholine, monoacylphosphatidylcholine and mixtures thereof.
  • the membrane phospholipid of component c) selected from the group consisting of soybean lecithin, soybean lecithin with about 80%, preferably more than about 90%, monoacylphosphatidylcholine content and enzyme modified soy lipid with about 60%, preferably more than about 70%, monoacylphosphatidylcholine content.
  • a suitable phospholipid of natural or synthetic origin is represented by the general formula
  • Ri is C10-20acyl
  • R 2 is hydrogen or C10-20acyl
  • R3 is hydrogen, 2-trimethylamino-l- ethyl, 2-amino-l-ethyl, Cl-4alkyl, Cl-5alkyl substituted by carboxy, C2-5alkyl substituted by hydroxy, C2-5alkyl substituted by carboxy and hydroxy, C2-5-alkyl substituted by carboxy and amino, or an inositol group or a glyceryl group, or a salt of such a compound.
  • Suitable sphingolipids and glycolipids of natural or synthetic origin are represented by the general formula 1 H — R.
  • X represents the ethylene or vinylen group or a bivalent group of the partial formula:
  • OH H H Ri is hydroxy, the phosphatidylcholine, the phosphatidylethanolamine group or hydroxy bound as ⁇ -glucoside to a mono- or oligosaccharide group or is an oligosaccharide group substituted by N-acetylneuraminic acid groups;
  • R 2 is C16-30-acyl, C16-30- ⁇ -hydroxyacyl or C16-30- ⁇ -hydroxyacyl, which is optionally esterif ied by a linoleic acid group;
  • the nomenclature used for the phospholipids (I) and (II) and the numbering of the carbon atoms (sn-nomenclature, stereospecific numbering) are in accordance with the recommendations made by the IUPAC-IUB Commission on Biochemical Nomenclature (CBN) in Eur. J. of Biochem. 79, 11-21 (1977) "Nomenclature of Lipids".
  • Ri and R 2 defined as C10-20acyl are preferably straight-chain C10- 20alkanoyl having an even number of carbon atoms and straight-chain C10-20alkenoyl having from one to three double bonds and an even number of carbon atoms.
  • Straight-chain C10-20alkanoyl Ri and R 2 having an even number of carbon atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
  • Straight-chain C10-20alkenoyl Ri and R 2 having from one to three double bonds and an even number of carbon atoms are, for example, 6-cis-, 6-trans-, 9-cis- or 9-trans-dodecenoyl, -tetra- decenoyl, -hexadecenoyl, -octadecenoyl or -icosenoyl, especially 9-cis-octadecenoyl (oleoyl), and also 9,12-cis-octadecadienoyl or 9,12,15-cis-octadecatrienoyl.
  • a phospholipid (1), wherein R 3 is 2-trimethylamino-l-ethyl, is referred to by the trivial name lecithin and a phospholipid (I), wherein R3 is 2-amino-l-ethyl, by the trivial name cephalin.
  • Suitable are, for example, naturally occurring cephalin or lecithin, for example cephalin or lecithin from soybeans or chicken eggs having different or identical acyl groups Ri and R 2 , or mixtures thereof.
  • the phospholipid (I) may also be of synthetic origin.
  • synthetic phospholipid is used to define phospholipids having a uniform composition in respect of Ri and R 2 .
  • Such synthetic phospholipids are preferably the above-defined lecithins and cephalins, wherein the acyl groups Ri and R 2 have a defined structure and are derived from a defined fatty acid having a degree of purity greater than approximately 95%.
  • Ri and R 2 may be identical or different and unsaturated or saturated.
  • Ri is saturated, for example n-hexadecanoyl
  • Naturally occurring defines (in definitions) a phospholipid (I) that does not have a uniform composition in respect of Ri and R 2 .
  • Such natural phospholipids are likewise lecithins and cephalins, wherein the acyl groups Ri and R 2 are structurally undefinable and are derived from naturally occurring or enzymatically derived fatty acid mixtures.
  • substantially pure defines (in definition) a phospholipid (I) having a degree of purity of more than 90% (by weight), preferably more than 95%, which can be demonstrated by means of suitable determination methods, for example by paper chromato- graphy, by thin-layer chromatography, by HPLC or by means of enzymatic colour testing.
  • R 3 defined as Cl-C4alkyl is, for example, methyl or ethyl. Methyl is preferred.
  • R 3 defined as Cl-5alkyl substituted by carboxy, C2-5alkyl substituted by hydroxy or C2- 5alkyl substituted by carboxy or hydroxy is, for example, 2-hydroxyethyl, 2,3-dihydroxy-n- propyl, carboxymethyl, 1- or 2-carboxyethyl, dicarboxymethyl, 2-carboxy-2-hydroxyethyl or 3-carboxy-2,3-dihydroxy-n-propyl.
  • R3 defined as C2-5alkyl substituted by carboxy and amino is, for example, 3-amino-3- carboxy-n-propyl or 2-amino-2-carboxy-n-propyl, preferably 2-amino-2-carboxyethyl.
  • a phospholipid (I) having those groups may be in salt form, for example in sodium or potassium salt form.
  • Phospholipids (I) wherein R3 is the inositol or the glyceryl group are known by the names phosphatidylinositol and phosphatidylglycerol.
  • the acyl radicals in the phospholipids (I) and in the other components are also customarily known by the names given in brackets:
  • a salt of the phospholipid (I) is pharmaceutically acceptable. Salts are defined by the exis- tence of salt-forming groups in the substituent R 3 and by the free hydroxy group at the phosphorus atom. The formation of internal salts is also possible. Alkali metal salts, especially the sodium salt, are preferred.
  • purified lecithin from soybeans for example of the LIPOID S 75 type
  • Phospholipids (I) of natural or synthetic origin wherein Ri represents C10-20acyl, R 2 represents hydrogen and R3 is as defined above, are known under the term lysophospholipids, particularly lysolecithin, wherein Ri represents C10-20acyl, R 2 represents hydrogen and R3 represents is 2-trimethylamino-l-ethyl.
  • sphingolipid or glycolipid of synthetic origin defines lipids (II), wherein segments of their molecular structure have been modified chemically, e.g. by hydration, transesterifica- tion, ester cleavage, esterification, substitution and other conventional process steps.
  • synthetic lipid also defines lipids (II) which are obtainable by total synthesis.
  • sphingolipid or glycolipid of natural origin defines lipids (II), which have only been submitted to purification processes, e.g. chromatographic separation methods, but have not been submitted to chemical modifications of their molecular structure.
  • sphingolipid or glycolipid comprises lipids, which are defined by terms such as ceramides, sphingomyelines, cerebrosides, or gangliosides. Ceramides and sphingomyelines are classified together under the term sphingolipids, whereas cerebrosides and gangliosides are classified together under the term glycolipids.
  • Ri is hydroxy.
  • Known ceramides are classified as ceramide 1, 2, 3, 4, 5, 6 I and 6 II.
  • the group of ceramides also comprises so-called synthetic questamides, e.g. questamide H, or so-called synthetic pseudo-ceramides, e.g. pseudo-ceramide SLE, and also lipids named ceramax.
  • ceramides which primarily occur in human skin are defined according to INCI rules (formerly CTFA) as ceramides 3.
  • 4-hydroxysphinganine phytosphin- gosin
  • 4-sphingenine sphingosine
  • Ri is the the phosphatidylcholine or the phosphatidylethanolamine group.
  • R 2 representing C16-, C18- and C24-acyl is preferably n-hexadecanoyl (palmitoyl), n-octa- decanoyl (stearoyl), n-tetracosanoyl (lignocerinoyl), 9-cis-octadecenoyl (oleoyl) or 9-cis- or 12-cis-octadecadienoyl.
  • R 2 representing C16-30-hydroxyacyl is preferably ⁇ -hydroxy-octadecanoyl or ⁇ -hydroxy- tetracosanoyl or a mixture thereof.
  • acid amides in this position formed with C2-10- ⁇ -hydroxycarboxylic acids, e.g. hydroxyacetic acid (glycolic acid), 2- hydroxypropionic acid (lactic acid), 2-hydroxysuccinic acid (malic acid), ⁇ -hydroxy- phenylacetic acid (mandelic acid) or mixtures thereof.
  • R 2 representing C16-30- ⁇ -hydroxyacyl, preferably in the sphingosine base phytosphingosine is, e.g. 23-octadecanoyloxytricosanoyl or 23-octadecanoyloxy-heptacosanoyl.
  • glycolipid (II) of the cerebroside type Ri represents hydroxy bound as ⁇ -glucoside to a mono- or oligosaccharide group which is optionally substituted by N-acetyl.
  • Representative monosaccharide groups are D-glucosyl and D-galactosyl, as well as N-acetyl- D-glucosamine and N-acetylgalactosamine.
  • a glycolipid (II) of the ganglioside-type Ri represents hydroxy, which is also bound as ⁇ - glucoside to an oligosaccharide group containing at least three hexosyl groups, which may be substituted by at least one N-Acetylneuraminic acid groups. These lipids are classified as gangliosides.
  • the compounds defined by the formula I are known and have been described in numerous textbooks and other references from biochemistry.
  • membrane lipid as defined above is combined with a pharmaceutically acceptable surfactant. It is to be understood that membrane lipids are regarded and used as biologically active compounds in cosmetic and some applications.
  • Suitable pharmaceutically acceptable surfactants include cationic, anionic or non-ionic surfactants.
  • a suitable cationic surfactant is N-benzyl-N,N-dimethyl-N-2-[2-(4-(l,l,3,3-tetramethylbu- tyl)-phenoxy-ethoxy]-ethylammonio chloride, N-benzyl-N,N-dimethyl-N-2-[2-(3-methyl-4- (l,l,3,3-tetramethylbutyl)-phenoxy)-ethoxy]-ethylammonio chloride (methylbenzethonium chloride), n-dodecyltrimethylammonio chloride or bromide, trimethyl-n-tetradecylammonio chloride or bromide, n-hexadecyltrimethylammonio chloride or bromide (cetyltrimethylam- monium chloride or bromide), trimethyl-n-octa
  • Ra represents a saturated or an unsaturated C6-C24hydrocarbon group
  • A represents C2-C8alkylene
  • m represents zero or one
  • B represents the sulphonate or sulphate group
  • Z+ represents a monovalent cation.
  • Preferred anionic surfactants are sodium or potassium C12-C20alkylsulphate, e.g. sodium or potassium-n-dodecyl, -tetradecyl, -hexadecyl or octadecylsulphate or -sulphonate, or sodium or potassium C12-C20alkylethersulphate, e.g.
  • Suitable non-ionic surfactants are selected from the group consisting of polyglycerol esters, polysorbates, mono- and diglycerides of fatty acids, propylene glycol esters, sucrose fatty acid esters and polyoxyethylene derivatives of sorbitan fatty acid esters. These surfactants are well known in the art and are commercially available.
  • Suitable polyglycerol esters consist of substantially pure polyglycerol fatty acid ester or of a mixture of different polyglycerol fatty acid esters, wherein the polyglycerol chain preferably contains up to and including 10 units of glycerol, which are esterified with 1-10 acid radicals of saturated or unsaturated carboxylic acids having an even number of 8-20 carbon atoms.
  • Suitable polyglycerol fatty acid esters having a uniformly defined structure are typically di- glycerol monocaprate, diglyceryl monolaurate, diglycerol diisostearate, diglycerol monoi- sostearate, diglycerol tetrastearate (polyglyceryl 2-tetrastearate), triglycerol monooleate (po- lyglyceryl 3-monooleate), triglycerol monolaurate, triglycerol mono stearate (polyglyceryl 3- stearate), triglycerol monoisosterate, hexaglycerol dioleate (polyglycerol 6-dioleate), hexaglycerol distearate (polyglycerol 6-distearate), decaglycerol dioleate (polyglycerol 10- dioleate), decaglycerol tetraoleate (polyg
  • CTFA nomenclature is given within the brackets. These products are commercially available under the registered trade mark Caprol® (trade mark of Karlshamns USA Inc., Columbus Ohio). Specific product names: CAPROL 2G4S, 3GO, 3GS, 6G20, 6G2S, 10G2O, 10G4O, 10G100, 10G10S. Further products are available under the names of DGLC-MC, DGLC-ML, DGLC-DISOS, DGLC-MISOS, TGLC-ML and TGLC-MISOS from Solvay Alkali GmbH, D- 3002 Hannover.
  • the mixture of different polyglycerol fatty acid esters is specified under names such as decaglycerol monooleate, dioleate, polyglycerol ester of mixed fatty acids, polyglycerol ester of the fatty acids, polyglycerol caprate, cocoate, laurate, lanolinate, isostearate or rizinolate and are commercially available under the registered trade mark Triodan® and Homo- dan®(trade mark of Grindsted Products, Grindsted Denmark), specific product names: TRIODAN 20, 55, R90 and HOMODAN MO; Radiamuls® (trade mark of Petrofina (FINA), Brussels Belgium), specific product name: RADIAMULS Poly 2253; under the name CAPROLPGE860 or ET, or under the registered trade mark Plurol®(trade mark of Gattefosse Etablmaschines, Saint-Priest, France), specific product name: PLUROL Stearique WL1009 or PLUROL Oleique WL1173.
  • Applicable are especially the product specifications published by the indicated producers on the data sheets of the specified product, in particular specifications such as mono- ester content, drop point, free glycerol, free fatty acid, iodine value, form, antioxidants, HLB value, properties and stability.
  • the cited polyglycerol fatty acid esters in particular conform to the requirements of number E475 of the EC food additives directive (EC directive 74/329) as well as the regulation of U.S. FDA Code 21 CFR_172.854.
  • suitable polyglycerol esters include triglyceryl monostearate, hexaglyceryl distearate, hexaglyceryl monopalimate, hexaglyceryl dipalmitate, decaglyceryl distearate, decaglyceryl monoleate, decaglyceryl dioleate, decaglycerol monopalmitate, decaglycerol dipalmitate, decaglyceryl monostearate, oc- taglycerol monoleate, octaglycerol monostearate and decaglycerol monocaprylate.
  • Suitable polysorbates include sorbitan fatty acid esters or polyoxyethylene sorbitan fatty acid esters.
  • Sorbitan fatty acid esters preferably consists of a sorbitan fatty acid ester which is substantially pure, or of a mixture of different sorbitan fatty acid esters, and the sorbitan skeleton is esterified with 1-3 acid radicals of a saturated or unsaturated straight-chain carboxylic acid having an even number of 8-20 carbon atoms.
  • the acid radical of a saturated carboxyHc acid having an even number of 8-20 carbon atoms which esterifies the sorbitan skeleton is preferably straight-chain with 12, 14, 16 and 18 carbon atoms, typically n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
  • the acid radical of an unsaturated carboxylic acid having an even number of 8-20 carbon atoms is preferably straight-chain with 12, 14, 16 and 18 carbon atoms, typically oleoyl.
  • Suitable sorbitan fatty acid esters are preferably sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate and sorbitan trioleate.
  • the above-mentioned partial fatty acid ester of polyoxyethylene sorbitan consists preferably of a substantiaUy pure ester of sorbitan or a mixture of different esters of sorbitan in which the structure of the fatty acid groups and the length of the polyoxyethylene chains may vary.
  • the hydrophiHc sorbitan is preferably etherified by three hydrophilic polyoxyethylene chains and esterified by a hydrophobic fatty acid group.
  • the sorbitan may, however, alternatively be etherified by only one or two polyoxyethylene chains and correspondingly esterified by two or three fatty acid groups.
  • the basic sorbitan structure is altogether substituted by a minimum of two and a maximum of three hydrophiHc groups, the term "hydrophiHc group" embracing the polyoxyethylene chains, whereas the fatty acid groups are hydrophobic.
  • the polyoxyethylene chain is linear and has preferably from 4 to 10, especiaUy from 4 to 8, ethylene oxide units.
  • the ester groups on the basic sorbitan structure are derived from a saturated or unsaturated, straight-chain carboxyHc acid having an even number of from 8 to 20 carbon atoms.
  • the ester group derived from that carboxyHc acid is preferably straight- chained having 12, 14, 16 or 18 carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n- hexadecanoyl or n-octadecanoyl.
  • the ester group derived from an unsaturated carboxylic acid having an even number of from 8 to 20 carbon atoms is preferably straight-chained having 12, 14, 16 or 18 carbon atoms, for example oleoyl.
  • the mentioned esters of sorbitan are in conformity with the data given in the British Pharmacopoeia (speciaHsed monograph) or Ph.Helv.VII.
  • the product specifications pubHshed by the mentioned manufacturers with the information on data sheets for the relevant product especiaUy specifications such as shape, colour, HLB value, viscosity, ascending melting point and solubiHty, apply.
  • Suitable partial fatty acid esters of polyoxyethylene sorbitan are commercially obtainable under the trademark Tween® of ICI Corp. and known by the chemical names polyoxyethyl- ene(20 or 4)sorbitan monolaurate (TWEEN 20 and 21), polyoxyethylene(20)sorbitan mono- palrr ⁇ tate or monostearate (TWEEN 40 and 60), polyoxyethylene(4 or 20)sorbitan mono- stearate or tristearate (TWEEN 61 and 65), polyoxyethylene (20 or 5)sorbitan monooleate (TWEEN 80 or 81) and polyoxyethylene(20)sorbitan trioleate (TWEEN 85).
  • sorbitan fatty acid esters and the polyglycerol fatty acid esters conform to the specifications Hsted in the British Pharmacopeia (special monography) or in Ph. Helv. VI. Applicable are especially the product specifications pubHshed by the indicated producers on the data sheets of the specified product, in particular specifications regarding e.g. form, colour, HLB value, viscosity, ascending melting point and solubiHty.
  • suitable polysorbates are obtainable from the reaction product of monoglycerides or sorbitan esters with ethylene oxides.
  • useful polysorbates include polyoxyethylene 20 mono- and diglycerides of saturated fatty acids, polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 20 sorbitan monooleate, polyoxyethylene 5 sorbitan monooleate, polyoxyethylene 20, sorbitan trioleate, sorbitan monopal itate, sorbitan monolaurate, propylene glycol monolaurate, glycerol monostearate, diglycerol monostearate, glycerol lac- tyl-palmitate.
  • Another group of suitable surfactants includes, with HLB values provided in brackets, includes decaglycerol monolaurate [15.5]; decaglycerol distearate [10.5]; decaglycerol dioleate [10.5]; decaglycerol dipalmitate [11.0]; decaglycerol monostearate [13.0]; decaglycerol monooleate [13.5]; hexaglycerol monostearate [12.0]; hexaglycerol monooleate [10.5]; hexaglycerol mono-shortening [12.0]; polyoxyethylene (20) sorbitan monolaurate [16.7]; polyoxyethylene (4) sorbitan monolaurate [13.3]; polyoxyethylene (20) sorbitan monopalmi- tate [15.6]; polyoxyethylene (20) sorbitan monostearate [14.9]; polyoxyethylene (20) sorbitan tristearate [10.5]
  • the HLB value for a surfactant is an expression of its hydrophiHc-HpophiHc balance, i.e., the balance of the size and strength of the hydrophiHc (polar) and HpophiHc (non-polar) groups of the surfactant.
  • Lactic acid derivatives include sodium stearoyl lactylate and calcium stearoyl lactylate.
  • a particularly preferred surfactant is d-Alpha tocopheryl polyethylene glycol 1000 succinate (TPGS)
  • surfactants or substances with amphipathic character like poloxamers polyethoxylated castor oil derivatives and protective coUoids like low- and high-molecular-weight components of, for example, gelatin, fish gelatin, starch, dextrin, plant proteins, pectin, gum arabic, casein, caseinate or mixtures of these, the protein-containing protective colloids, in particular non-gelling low-molecular-weight protein hydrolysates and higher-molecular- weight gelling gelatins being preferred.
  • poly(vinylalcohol), polyvinylpyrroHdone, methyl cellulose, carboxymethyl ceUulose, hydroxypropyl ceUulose and alginates can also be used.
  • the surfactants suitable for the invention are not limited to the examples provided above. In general, the weight ratio of surfactant to support material is less or equal to 1 : 2, regardless of drug content. Where TPGS is employed as the preferred surfactant, it may be present in excess of the active compound.
  • Suitable pharmaceuticaUy acceptable additional excipients are added to the carrier composition in such an amount as to make up 100% by weight together with the amounts of components a), b) and c) as weU as of the therapeutic agent or combination thereof. Additional excipients can be present in the composition in amounts of 0% to c.75% by weight. Additional excipients depend on the choice of the pharmaceutical dosage form.
  • PharmaceuticaHy acceptable diluents are added to Hquid dosage forms, such as drops, suspensions or capsule fillings, typicaUy ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, butylenes glycol , hexalene glycol, or mixture thereof, glycerol or water, or mixtures thereof.
  • a suitable pharmaceutical diluent is a carrier Hquid, e.g. water, which is optionaHy admixed with a C2-C4-alkanol, especiaUy ethanol, and is present in the composition in the degree of purity necessary for the intended pharmaceutical or cosmetic administration.
  • Hquid e.g. water
  • a carrier Hquid e.g. water
  • the carrier Hquid ethanol is optionaUy admixed as C2-C4-alkanol when parenteral dosage forms are intended. In that event ethanol is present, ethanol has the degree of purity (at least 96%) prescribed for injection formulations. The proportion of ethanol for injection formulations may vary within wide limits from about 1.0% to about 10.0%. For topical dosage forms or cosmetic uses, ethanol, isopropanol or mixtures thereof may be optionaUy admixed as C2- C4-alkanol. The proportion of C2-C4-alkanol for topical formulations or cosmetic uses may vary within wide limits from about 0.1% to about 10.0%, preferably 0.1% to 2.0%. Other suitable excipients are hydrophiHc and HpophiHc polymers which are used as fiUers bulking agents and viscosity improvers. Examples are the natural gums, ceUulose derivatives etc.
  • Typical additives may be present in the composition, which are characteristic for the intended pharmaceutical dosage form or cosmetic uses. They have a degree of purity in ac- cordance with the regulations of the national pharmacopoeias mentioned above. Depending on the intended use, additives may be water soluble or Hpid soluble. Suitable additives /excipients include those that are useful for the preparation of o/w, w/o, w/o/w emulsions, gels, ointments, creams, oUs, lotions, foams, or sprays. The addition of preserving agents, antioxidants, stabilizers or softening agents is recommended.
  • a preferred additive in topical pharmaceutical and cosmetic compositions is cholesterol or a corresponding salt thereof, e.g. cholesterol sulphate with the purity necessary for the intended cosmetic or pharmaceutical administration.
  • Suitable additives for pharmaceutical and particularly cosmetic compositions are also free fatty acids derived by conventional ester cleavage from the above-mentioned triglyc- erides (III), surfactants, e.g. anionic, cationic, or amphoteric, gel-forming agents, emulsifiers, e.g. ethoxylated fatty alcohols, hydrogenated ethoxylated castor oUs, partial esters of fatty acids and modified fatty acids with glycerol, polyglycerol, and sorbitol, orthophosphoric acid esters, or siHcone surfactants, HpophiHc constituents, e.g.
  • surfactants e.g. anionic, cationic, or amphoteric
  • gel-forming agents emulsifiers, e.g. ethoxylated fatty alcohols, hydrogenated ethoxylated castor oUs, partial esters of fatty acids and modified fatty acids with
  • soHd, semisolid, and Hquid hydrocarbons natural oUs and waxes, suicone and volatile siHcone oU, guerbet alcohols, fatty acid esters, isostearic acid derivatives, co-emulsifiers, thickeners, gelling agents, foam stabiHzers, fat-restoring substances, pearl-lustre and turbidity agents, preservatives, dyes, colored pigments, perfume oUs, and preferably Ught filters (sunscreens).
  • excipients can also be added to oral dosage form, e.g. capsule fillings, e.g. semi-synthetic or synthetic, substantiaUy pure triglyceride or a pharmaceuticaUy acceptable triglyceride of natural origin.
  • a triglyceride of natural origin is preferred, for example groundnut, sesame, sunflower, oHve, maize kernel, soybean, castor, cottonseed, rape, thistle, grapeseed, fish or coconut oU.
  • additives include for example preservatives, typicaUy benzyl alcohol, ethanol, p-hydroxybenzoate, sorbic acid; antioxidants, typically tocopherols, butylhydroxyanisol, butylhydroxytoluene, ascorbic acid, ascorbylpalmitate; stabUisers, typi- cally citric acid, tartaric acid, EDTA, flavourings or fragrances.
  • Gelatin capsules and the like are suitably fiUed with conventional plasticisers to stabiHse the gelatin sheU.
  • excipients are typically sorbitol, sorbitan, polyvinylpyrrolidone, hydroxy propylmethyl cellulose (HPMC), hydroxypropyl ceUulose, methyl ceUulose or colloidal siHcon dioxide.
  • HPMC hydroxy propylmethyl cellulose
  • a further object of the invention is to prepare a composition comprising a HpophiHc biologi- caUy active compound with low water solubiHty in molecular association or dispersion in at least one membrane Hpid sequestered in the interior of a porous support material without using organic solvents.
  • HpophiHc compound This is done by partitioning a HpophiHc compound into an aqueous lipid suspension preferably using a high shear mixer.
  • the compound is intercalated in the HpopMHc domain of the Hpid aggregates which is then loaded into the support material, foUowed by removal of excess water.
  • the compound remains in molecular association with the Hpid and is sequestered in the pores of the support material.
  • the Hpids used in this case are a mixture of a monoacyl Hpid and diacyl Hpid form natural soy or egg Hpids.
  • the HpophiHc compound is first finely dispersed or preferably dissolved in a suitable solvent or solvent mixture , which may include a membrane Hpid and/ or surfactant.
  • a suitable solvent or solvent mixture which may include a membrane Hpid and/ or surfactant.
  • the solution or lipid suspension is loaded into the pores of the support material, preferably by means of reduced pressure or vacuum to ensure maximum adsorption on the internal surfaces lining the pores after solvent removal. Adequate deposition into the interior spaces of the particle agglomerates may also be obtained by e.g. spray drying and fluidised bed drying.
  • the role of the solvent/ s is to dissolve the compound with low water solubiHty and carry it into the pores of the support material.
  • the solvent/ solvent mixture employed is a volatile solvent with low viscosity.
  • a surfactant is also included to reduce surface tension effects, de-aerate the surfaces of the material and aUow maximum penetration into the pores.
  • the method employed enables the compound to be carried into the internal pores of the agglomerates either in solution or in ultra fine form when the solvent is removed. In contrast, solutions and suspensions in viscous Hquids including those using hot melt techniques are less efficient.
  • the composition yields a highly dispersive solution or an ultra fine suspension of the drug, optionaUy in association with a Hpid/ surfactant, after release from or dissolution of the support material, compared to drug particles on their own.
  • This is Ulustrated in the release profiles shown in Fig 1.
  • the agglomerates have an internal surface area greater than 25 m 2 /g. The fact that the HpophiHc compound remains in highly dispersive ultra fine precipitate inside the minute pores of the absorbent support material is surprising.
  • the precipitate may be constrained by the very smaU pore size and stabiHsed in ultra fine possibly amorphous form/s inside the channels.
  • the HpophiHc drug may remain molecularly dispersed in a second component which is a membrane lipid and/ or surfactant.
  • the ultra fine pores of the support material may be sufficient to physicaUy prevent or constrain crystallisation of the drug to larger crystals. Therefore it may only be necessary to make sure that the drug is deposited or absorbed as a solution into the pores of the support material in the first instance. The solvent, with or without the Hpid is removed, leaving behind an adsorbed material.
  • primary loading is carried out by firstly impregnating the pores of a blank or unloaded support material with the compound associated in membrane Hpid and/ or surfactant, or dissolved in a solvent alone, which term includes aqueous media and mixtures thereof.
  • the solvent is then removed using any appropriate drying method e.g. spray drying, vacuum, or freeze drying, etc., to obtain a loaded particulate composition.
  • secondary loading may be carried out by firstly preparing a powder blend comprising the unloaded porous support material, compound with low water solubiHty and optionaUy membrane lipid and /or surfactant. In this method, the compound is loaded into the pores of the support medium foUowing addition of a suitable solvent/ solvent mixture.
  • the composition obtained may be used as such as a free flowing powder or a Hquid suspension.
  • the composition may also be further processed by extrusion into granules, and compacted into tablets by addition of suitable excipients commonly used in solid dosage forms.
  • Organic and inorganic materials widely used as anti-caking agent, disintegrant, filler, adsorptive, pulverizing and moulding excipient may be used.
  • the support material dissolves in the low pH conditions of the upper GI tract to release the compound in ultra fine form or in molecular dispersion.
  • dissolution takes place inside the body after oral administration.
  • the support material dissolves in the GI tract, releasing the HpophUic com- pound from the interior pores of the support material. If the compound is sequestered as a solution in Hpid, transfer into the surrounding medium wiU be instant. Even if it is not, because of the ultra fine form, dissolution wUl be much improved.
  • a powder composition comprising the compound sequestered in ultra fine form in a support material may be further processed by contact with acid medium in a suit- able container. By this treatment the support material is dissolved and the HpophUic compound may be harvested or collected as ultra fine powder. The powder has improved solubiHty and dissolution profile and may be processed further into suitable dosage forms.
  • a further embodiment of the invention relates to a mixture, e. g. a placebo mixture, suitable for the preparation of composition for improving the dispersibiHty of biologicaUy active compounds having low water solubUity, which comprises b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; c) A membrane Hpid; or, in the alternative a membrane Hpid and/ or at least one pharmaceuticaUy or cosmeticaUy acceptable surfactant; and, optionaUy, d) Additional pharmaceuticaUy acceptable excipients.
  • a mixture e. g. a placebo mixture, suitable for the preparation of composition for improving the dispersibiHty of biologicaUy active compounds having low water solubUity, which comprises b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; c) A membrane Hpid; or, in the alternative a membrane Hpid and/ or at least one pharmaceuticaUy or cosmetic
  • the mixture defined above comprises compositions, wherein the component b), the porous particulate support material, is present
  • the mixture comprising the components b), c) and d) is obtainable by applying the above- mentioned methods and is suitable for secondary loading or dispersion of any agent of low water solubiHty, e.g. nutritional agents, vitamins, diagnostic agents or enzyme preparations.
  • any agent of low water solubiHty e.g. nutritional agents, vitamins, diagnostic agents or enzyme preparations.
  • a HIV protease inhibitor (MW: 516.2, empirical formula: C 20 Hi6Br 2 N6 ⁇ solubUity: ⁇ 0.010 ⁇ g/ml), and 70 mg of TPGS are dissolved by stirring in 105 g of a (25/75) mixture of ethanol 96% and dichloromethane.
  • the solution is added in fractions under stirring to 7 g NEUSILIN Grade US2 (Fuji Chemicals).
  • the addition of the fractions is repeated until complete addition of the solution to NEUSILIN.
  • the solvent mixture is removed under vacuum for 180 min at room temperature after addition of each fraction.
  • the resulting free flowing powder is fiUed into 25 gelatin capsules OO, each containing 300 mg of powder.
  • the capsules are suitable for oral administration.
  • porous maltodextrin (PineflowTM, Matsutani Chemical Industry Ltd) is equaUy suitable.
  • the content of one capsule is added to one Hter of 0.1 M HCl in a dissolution apparatus as described in USP 24. After one hour stirring at 37°C ultra fine particles of HIV protease inhibitor is obtained.
  • the HIV protease inhibitor is dissolved in a solution of 35 mg TPGS (instead of 70 mg TPGS), and VP 815, an enzyme modified soy Hpid with 60% monoacyl Hpid content (Lipoid KG, Ludwigshafen, FRG).
  • cyclosporin A (Refarmed Chemical Ltd. Lugano, CH) is dissolved under stirring in 9.0 g ethanol 90%. The solution is added under stirring to 10 g NEUSILIN Grade US2 (Fuji Chemicals). The alcohol is removed under vacuum for 180 min at room temperature. The resulting free flowing powder is fiUed into 32 gelatin capsules OO, each containing 300 mg of powder.
  • the capsules are suitable for oral administration.
  • the content of one capsule is added to one Hter 0.1 M HCl containing 0.5% sodium dodecyl sulphate in a dissolution apparatus as described in USP 24 to one Hter 0.1 M HCl containing 0.5% sodium dodecyl sulphate. After one hour of stirring at 37° C an ultra fine suspension of cyclosporin particles is obtained.
  • Example 5 lg cyclosporin A, practicaUy insoluble in water, (Refarmed Chemical Ltd. Lugano, CH) and 100 mg of Soybean lecithin S 75 (Lipoid KG, Ludwigshafen, FRG) are dissolved under stirring in 8.9 g ethanol 96%. The solution is added under stirring to 10 g NEUSILIN Grade US2 (Fuji Chemicals) The alcohol is removed under vacuum for 180 min at room temperature. The resulting free flowing powder is fiUed into 32 gelatin capsules OO, each containing 300 mg of powder. The capsules are suitable for oral administration. For characterisation purposes, the content of one capsule is added to one litre 0.1 M HCl in a dissolution apparatus as described in USP 24. Alter one hour stirring at 37° C an ultra fine dispersion of cyclosporin is obtained.
  • Example 6 lg cyclosporin A, practicaUy insoluble in water, (Refarmed Chemical Ltd. Lugano, CH) and 3g VP 814 Soybean lecithin with 80% by weight monoacyl lecithin (Lipoid KG, Ludwigshafen, FRG) are dissolved in 6 g ethanol absolute.
  • the Hpid solution is stirred into 10 g NEUSILIN Grade US2 (Fuji Chemicals).
  • the alcohol is removed under vacuum for 180 min at room temperature.
  • the resulting free flowing powder is fiUed into 32 gelatin capsules OO, each containing 300 mg of powder.
  • the capsules are suitable for oral administration.
  • the content of one capsule is added to one litre of 0.1 M HCl in a dissolution apparatus as described in USP 24. After one hour stirring at 37° C an ultra fine suspension of cyclosporine associated in Hpid particles is obtained.
  • Examples 7, 8 and 9 are carried out in a manner similar to Examples 4, 5 and 6, but instead of 10 g NeusilinTM, 20 g of Fujicalin® Grade SG from Fuji Chemicals is used.
  • Example 10
  • a peripheral benzodiazepine receptor Hgand (MW: 394.86, empirical formula: C21H19C1N4O2, solubiHty: 1 ⁇ g/ml)
  • TPGS d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate
  • the resulting solution is loaded in stages to 2 g NeusilinTM Grade US2 from Fuji Chemicals.
  • the solvent is removed under vacuum for 180 min at room temperature after addition of each fraction. This procedure was repeated until aU the solution was impregnated into Neusilin. This is an example based on primary loading as described.
  • the resulting free flowing powder is fiUed into 6 gelatin capsules OO, each containing 300 mg of powder.
  • the capsules are suitable for oral administration.
  • the content of one capsule is added to one liter of 0.1 M HCl in a dissolution apparatus as described in USP 24. After one hour stirring at 37 ° C a finely dispersed suspension of HIV protease particles is obtained.
  • DispersabUity of the loaded composition of Example 12 is compared with the drug alone (particle size ⁇ 10 ⁇ m) at a concentration of 0.1 mg/ml using 900 ml of 10 % w/v sodium dodecyl sulphate and 0.1 M HC in a 1 Htie dissolution beaker (USP XXIV) stirred with a paddle at 50 rpm at 37°C.
  • the amount of drug exposed to the dissolution medium is three times lower than the maximum solubiHty of the drug substance.
  • aHquots of the incubation media are taken and after fUtration through a 0.45 ⁇ m pores size fUter, drug concentration is determined using a specific HPLC method
  • the dissolution rates of the two samples are iUustrated in Fig 1. It is seen that 96 wt % of the compound with low water solubiHty sequestered inside the pores of the porous support material disperses and dissolves within 6 min. compared to the drug alone which takes 45 min. under very similar conditions to reach the same level of dissolution.

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Abstract

The invention relates to compositions for improving the solubility or dispersibility of biologically active compounds having low water solubility in molecular association or in ultra fine form. The compositions comprise a biologically active compound having low water solubility in combination with a porous particulate support material capable of incorporating within its pores the biologically active compound.

Description

COMPOSITION COMPRISING LOW ATER SOLUBLE COMPOUNDS ITHIN POROUS CARRIERS
The present invention relates to compositions for improving the solubility or dispersibility of biologically active compounds having low water solubility in molecular association or in ultra fine form. A specific object of the invention is to improve the dissolution rate or dispersive properties of a lipophilic compound with low water solubility and its bioavailability, without using energy intensive methods for particle size reduction or relying on the presence of high levels of solvents in the composition. A major benefit of the present invention is that extensive milling procedures, such as wet-milling to obtain sub-micron drug particles are avoided. The lipophilic compound is in ultra fine form with large surface areas with improved dispersibility and increased dissolution profile compared to micronised drug particles. The biologically active compound with low water solubility is held inside the pores of a suitable support material in association or solution in a suitable membrane lipid and/ or surfactant or is present as ultrathin layer(s) and/ or ultrafine amorphous particles with or without lipid and/ or surfactant. The compositions may be further processed into suitable dosage forms, such as semi-solid and solid dosage forms, with minimum effort.
Improvement of dispersibility and dissolution rates employ size reduction methods for obtaining small particles of water insoluble compounds, and/ or require fillers, diluents, anti- caking and adsorptive aids to stabilise the external surfaces of micronised drug particles to prevent agglomeration. Typically, energy mills are used to micronise active materials with the aim of improving solubility from the large external surface areas created. Preventing clumping and crystal growth of micronised or precipitated particles is a problem and in reality the methods often fail to produce significant increases in bioavailability.
US-A-5,091,188 discloses injectable compositions in which insoluble or poorly soluble drugs in powder form are stabilized against agglomeration during storage by treating the external surface of the particles with one or more layers of phospholipid.
WO 99/49846 discloses compositions and procedures that yield sub-micron and micron size stable crystalline particles of water-insoluble drugs. In order to avoid particle growth and aggregation or flocculation of the particles in suspension, the surfaces are treated with phospholipid, a charged surface modifier and a block copolymer. However, high shear mixing with multiple passes through a micro fluidiser is necessary to produce particles of sufficiently small size.
WO 99/65469 further discloses submicron particles of water-insoluble drugs, prepared simultaneously by stabilising microparticulate suspensions of the drug with surface modifier molecules e.g. a phospholipid, by rapid expansion into an aqueous medium from a compressed solution of the compound and surface modifiers in a liquified gas. The particles of the drug are surface stabilised in the suspension in order to prevent agglomeration.
EP-A-0 795 585 discloses a process for preparing finely divided particulate suspensions of a retinoid or carotenoid in a volatile, organic solvent mixed with aqueous medium in the presence of a physiologically compatible emulsifying agent, e.g. lecithin.
The prior art also describes methods of preparing co-precipitates with or without lipids with the aim of improving solubility. Thus, the preparation of lipid-drug co-precipitates using diacyl phospholipids to increase the dissolution behaviour of poorly water soluble drug solvates, and the possibility of modifying drug release from such dispersions by incorporating small amounts(<0.05%) of poly vinyl pyrrolidone is described in J. Pharm. Sci. 81, 283-286 (1992). The compositions are prepared essentially by co-precipitation which results in the incorporation of lipid in the crystalline structure of the solvate. The residual solvent trapped in the solvate crystals is given as a possible reason for the improved solubility of the poorly water soluble compound. PCT/US86/00637 discloses the use of non-esterified fatty acids and monoglycerides together with minor amounts of a monoacyl lipid (lysophosphatidylcholine) to form lipid particles which show improved oral absorption for various lipophilic compounds. Improved oral absorption is claimed to be due to the unique properties of the mixture.
More recently, the use of mixtures of monoacyl and diacyl lipids which can form carrier systems based on a wide range of vesicular and non vesicular structures to obtain superior bioavailability has been disclosed in WO 98/58629, WO 99/23901, WO 99/44642 and PCT/ GB99/ 04070. For example, WO 98/58629 describes lipid compositions comprising at least one monoacyl lipid, e.g. monoacyl phospholipid and mixtures of monoacyl and diacyl phospholipids that are effective in carrying lipophilic compounds in molecular form. The compositions may be a waxy solid, a paste-like material or a viscous fluid suitable for filling into hard or soft gelatin capsules.
WO 00/38655 describes a dosage form comprising a plurality of particles having interior pores and a liquid, active agent formulation in the pores to retain substantially all of the liquid active agent formulations in the pores during compaction. The method explicitly requires the liquid to remain inside the pores dissolved in a non volatile liquid such as propylene glycol. The procedure used is for absorbing liquids described in the Neusilin™ brochure (Fuji Chemical). WO 00/38655 is concerned with powder compositions containing absorbed liquid solutions/ suspensions and a method to modify the dissolution characteristics of both hydrophilic and lipophilic compounds. US 20010009677 discloses a solid oral dosage form comprising a solid carrier of magnesium alumina silicate, an effective amount of a lipophilic stanol ester and a mixed micelle surfactant system to solubilise the compound using a hot melt method, which coats and deposit the compound on the external surfaces of the core particles. It is silent with respect to the lipophilic compound being sequestered and maintained in ultra fine form or in molecular solution inside the pores of the carrier. Furthermore, the compositions do not comprise membrane lipids or a method of introducing the compound into the pores of a support medium by means of a solvent with or without membrane lipid and/ or surfactants, followed by removal of the solvent. US-A-5,624,687 discloses a soluble salt of compounds with low water solubility at elevated pH dissolved in an organic solvent mixture containing an enteric base coated onto core particles like magnesium alumina silicate to make a solid quick-dissolution preparation with increased oral bioavailability. It is claimed that the compound is deposited as a solid solution in an enteric base on the exterior surfaces of the core particles from sprayed droplets. The core particles include calcium hydrogen phosphate, sucrose, lactose, starch and crystalline cellulose. It does not disclose the sequestration of drugs which have low water solubility at neutral pH in the internal pores of a porous support medium in ultra fine or molecular form with or without membrane lipids and/ or surfactants.
Pharmaceutical Development and Technology, 6(4), 563-572 (2001) describes a combination of solid dispersion and surface adsorption techniques using hot melts at temperatures of 90° C to cover the surface of adsorbent particles. The solid dispersion carrier is a surfactant which solubilises the drug without using a solvent and the increase in dissolution was attributed to the formation of a solid solution on the surface of the particles. The method does not involve a solvent to reach the internal pores of the carrier, from where it is removed. Subject matter of the present invention is a composition, particularly a pharmaceutical or cosmetic composition, for improving the dispersibility of biologically active compounds having low water solubility regardless of pH which comprises, a) A biologically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; c) A membrane lipid; or, in the alternative, a membrane lipid combined with a pharmaceutically acceptable surfactant; and, optionally, d) Additional pharmaceutically acceptable excipients. In the description of the present invention the following definitions apply:
"Compounds" are biologically active substances that have a physiological and/ or pharmacological effect. They are also referred to as drugs or therapeutic agents and include nutrition agents, food and feed additives, cosmetic and diagnostic substances. "Low water solubility" means any compound that requires more than 10 parts of water to dissolve 1 part of the compound. It spans the definitions between sparingly soluble (from 10 to 30) to very slightly soluble (from 1000 to 10 000) and practically insoluble or insoluble (10 000 and over) as defined in USP 24. The term includes hydrophobic or lipophilic or amphipathic compounds. "Lipid" refers to membrane lipids, which include phospholipids, glycolipids, ceramides, gangliosides and cerebrosides. The term as used herein refers to a single type as well as to mixtures thereof.
"Lipid suspension" refers to an aqueous dispersion of lipid particles.
"Support material" refers to highly porous clusters or agglomerates of small particles held together by physical forces creating large internal surfaces in the inter-particulate pores or channels which are accessible to solvents.
"Ultra fine form" implies that the compound is in the finest state of subdivision possibly as amorphous particles or ultrathin layer but not in molecular dispersion or solution in the pores, or after hydration and contact of the composition with aqueous media. "Adsorption" refers to the containment or sequestering of a compound on the external as well as internal surfaces lining the pores of the support material.
According to a specific embodiment of the invention "adsorption" refers to the containment, impregnation or sequestering of a compound "essentially" (more than 90%, particularly 95%) on the external as well as internal surfaces lining the pores of the support material. "Ultrafine dispersion" is achieved if more than 50% of the drug is able to pass a 0.45 micron filter after incubation of the composition in a suitable dissolution medium, such as 0.5% SDS (sodium dodecyl sulphate) in 0.1N HC1 or another dissolution media used for dissolution testing.
COMPOSITION The composition according to the present invention, as defined above, has improved dispersibility and dissolution profiles and may be used as such, or preferably converted to free flowing powders or granules with excipients such as sugars and polymers which increase the bulk density. The composition may also be processed further by known methods, such as extrusion, and compacted into tablets or filled into hard gelatine capsules or the like by addition of suitable additional excipients commonly used in solid dosage forms. Organic and inorganic materials widely used as anti-caking agents, disintegrants, fillers, adsorbents, pulverising or moulding excipients may be used. Alternatively, the composition may be suspended in a liquid vehicle for topical applications. After oral administration, the support material dissolves at least partially in the low pH conditions of the upper Gl-tract to release the compound in ultra fine form or in molecular dispersion. The key function of the support material is to enable a compound with low water solubility to be deposited inside the pores in highly dispersive ultrafine form. The prior art only describes the use of solid particulate carriers either to absorb liquids to facilitate handling and storage or as diluents and core materials coated on the external surfaces of the particles by a solid compound.
In one embodiment of the invention, dissolution takes place inside the body after oral ad- ministration. It is believed that the support material impregnated with lipophilic substance with or without surfactant and/ or lipid readily disperses and/ or dissolves in the GI- tract, releasing the lipophilic compound from the pores. This improves the dissolution profile of a compound with low water solubility.
According to another embodiment of the invention, a powder composition comprising the compound sequestered in ultra fine form inside a support material may be further treated with acid medium in a suitable container. By this treatment the support material is dissolved and the lipophilic compound may be harvested or collected as ultra fine powder. The powder has improved dispersibility and dissolution profiles and may be processed further into suitable dosage forms. An alternative and preferred embodiment of the invention relates to a pharmaceutical or cosmetic composition for improving the dispersibility of biologically active compounds having low water solubility, which comprises a) A therapeutically or cosmetically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; c) At least one membrane lipid; and, optionally, d) Additional pharmaceutically acceptable excipients. Another alternative embodiment of the invention relates to a pharmaceutical or cosmetic composition for improving the dispersibility of biologically active compounds having low water solubility, which comprises a) A therapeutically or cosmetically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; c) At least one membrane lipid combined with at least one pharmaceutically acceptable surfactant; and, optionally, d) Additional pharmaceutically acceptable excipients.
An example of the invention relates to a pharmaceutical composition for improving the dispersibility of a HIV-protease inhibitor, particularly a HIV-1-protease inhibitor of low water solubility, which comprises a) A therapeutically effective amount of a HIV protease inhibitor; b) A porous particulate support material capable of incorporating within its pores the biologically active compound, and optionally; c) At least one membrane lipid and/ or at least one a pharmaceutically acceptable surfactant; and, optionally, d) Additional pharmaceutically acceptable excipients. Another selective and preferred embodiment of the invention relates to a pharmaceutical composition for improving the dispersibility of cyclosporins, particularly cyclosporin A or G, which comprises a) A therapeutically effective amount of cyclosporin A; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; and, optionally; c) A pharmaceutically acceptable surfactant; or, in the alternative, a pharmaceutically acceptable surfactant combined with a membrane lipid; and, optionally, d) Additional pharmaceutically acceptable excipients.
A further embodiment of the invention relates to a pharmaceutical composition for improving the dispersibility of peripheral benzodiazepine receptor ligand with activity in neuro-degenerative diseases which comprises: . . J . .
a) A therapeutically effective amount of a peripheral benzodiazepine receptor ligand with activity in neuro-degenerative diseases; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; and, optionally; c) A pharmaceutically acceptable sturfactant; or, in the alternative, a pharmaceutically acceptable surfactant combined with a membrane lipid; and, optionally, d) Additional pharmaceutically acceptable excipients.
Additional embodiments of the invention are
(i) Pharmaceutical and cosmetic dosage forms comprising a porous support material and organic solutions/ aqueous suspensions containing a drug and a surfactant and/ or a membrane lipid as a minor component(s) as compared to the amount of the support material, and which yields after hydration and/ or dissolution of the carrier (dosage form) in-vivo or in-vitro, ultra fine drug particles associated with surfactant or a mixture of surfactant and lipids, possibly in the amorphous state; or
(ii) A drug and surfactant and/ or a membrane lipid as (a) minor component(s) as compared to the amount of the support material, which yields after dissolution of the carrier (dosage form) in-vivo or in-vitro ultra fine drug particles associated with surfactant or a mixture of surfactant and lipids, possibly in the amorphous state.
METHOD
In another aspect, the invention relates to a process for the preparation of a pharmaceutical or cosmetic dosage form, as defined above, which is characterised in that in a suitable solvent or solvent mixture a homogeneous dispersion is prepared, which comprises, a) A biologically effective amount of at least one biologically active compound having low water solubility; b) A porous particulate support material capable of incorporating within its pores the biologically active compound; and, optionally, c) A membrane phospholipid; and/ or a pharmaceutically acceptable surfactant; d) Additional pharmaceutically acceptable excipients.
Component d) may be added during loading and impregnation of the compound with low water solubility using a solvent or solvent mixture, followed by drying or solvent removal. Component d) may be added during or after loading and impregnation of the compound. The homogeneous dispersion is converted to a dosage form suitable for pharmaceutical or cosmetic administration.
The process comprises the following inventive process embodiments, wherein the component a), biologically active compound having low water solubility is present in combination with the component b), the porous particulate support material, the presence of components a) and b) combined with
• A membrane lipid, as defined below, or
• A membrane lipid and a pharmaceutically or cosmetically acceptable surfactant as defined below; or
• A pharmaceutically or cosmetically acceptable surfactant as defined above; is optional. The presence of additional pharmaceutically or cosmetically acceptable excipients, component d), is optional in any of the embodiments described above.
A further embodiment of the invention relates to a method for improving the dispersibility of biologically active compounds having low water solubility, which comprises i) Dissolving or dispersing a biologically effective amount of at least one biologically active compound having low water solubility in a suitable volatile pharmaceutically acceptable solvent; ii) Dissolving or dispersing in the compound solution at least one membrane phospholipid; or, in the alternative, at least one pharmaceutically acceptable surfactant; or mixture of said membrane lipid and surfactant, optionally, additional pharmaceutically acceptable excipients; and iii) Adding the solution to a porous particulate support material capable of incorporating within its pores the biologically active compound; followed by removal of the solvent, to produce a composition with increased aqueous dispersibility of said compound.
An alternative method relates to a method for improving the dispersibility of biologically active compounds having low water solubility, which comprises j) Dissolving or dispersing a biologically effective amount of at least one biologically active compound having low water solubility in a suitable volatile pharmaceutically acceptable solvent; ii) Adding the solution or dispersion to a porous particulate support material capable of incorporating within its pores the biologically active compound; followed by removal of the solvent, to produce a composition with increased aqueous dispersibility of said compound and optionally other excipients. Another embodiment of the invention relates to a specific method for preparing said dosage forms, which includes the following process steps: i) dissolving or dispersing drug in a solvent or solvent water mixture or aqueous medium containing, optionally at least one membrane lipid and/ or pharmaceutically acceptable surfactant. ii) adding the suspension or solution to a porous support material; iii) optionally followed by removal of said water or solvent.
In another aspect, the present invention relates particularly to processes and methods for providing:
(A) A composition for improving the dispersibility, dissolution and the bioavailability of a biologically active compound having low water solubility comprising, a) A therapeutic amount of a biologically active compound having low water solubility; b) A particulate porous support material capable of sequestering the biologically active compound within its pores; c) At least one membrane lipid or a mixture of membrane lipid and surfactant and, optionally, d) Other pharmaceutically acceptable excipients.
(B) A composition for improving the dispersibility, dissolution and the bioavailability of a biologically active compound having low water solubility comprising, a) A therapeutic amount of a biologically active compound having low water solubility; b) A particulate porous support material capable of sequestering the biologically active compound within its pores; optionally c) At least one membrane lipid and/ or a mixture of membrane lipid and surfactant ; d) Other pharmaceutically acceptable excipients.
C) A composition for improving the dispersibility, dissolution and the bioavailability of a biologically active compound having low water solubility comprising, a) A therapeutic amount of a biologically active compound having low water solubility; b) A particulate porous support material capable of sequestering the biologically active compound within its pores; c) At least one surfactant, and optionally at least one membrane lipid and, optionally, d) Other pharmaceutically acceptable excipients.
Further embodiment of the invention are: • The compositions, in which the surf actant is selected from the group consisting of d-α-tocopheryl polyethylene glycol 1000 succinate, a poloxamer, polyethoxylated castor oil derivative and a protective colloid
• The compositions, wherein the weight ratio of the surfactant to active compound with low water solubility, or preferably, surfactant or surfactant lipid mixture to support material is less or equal to 1 : 2 by weight
• A dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before and comprising a therapeutic amount of a biologically active compound having low water solubility • A dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before and comprising a therapeutic amount of a biologically active compound having low water solubility and in which the support material is amorphous aluminometasilicate or calcium silicate in particulate form • A dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before comprising a therapeutic amount of a biologically active compound having low water solubility; and in which the support material is amorphous Al2O3-MgO-1.7 SiO-7H2O or Ca2SiO4 or CasSiOs or a mixture of Ca2SiO4 and Ca3SiOs in particulate form
• A dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before comprising a therapeutic amount of a biologically active compound having low water solubility and in which the support material is dibasic anhydrous calcium phosphate
• A dosage form for administration of a biologically active compound having low water solubility which is derived from further processing a composition as mentioned before comprising a therapeutic amount of a biologically active compound having low water solubility, which after (partial) dissolution of the porous support in 0.1 M HCL containing 0.5% sodium dodecylsulphate results in a molecular association or solution of the biologically active compound having low water solubility in the membrane lipid
• Any one of the mentioned dosage forms for peroral, rectal or topical application
• A method for the preparation of a composition for improving the dissolution and the bioavailability of a biologically active compound having low water solubility wherein, A biologically active compound having low water solubility and surfactant and optionally a lipid are first finely dispersed or preferably dissolved in a suitable solvent,
The solution or suspension is mixed with a porous support material, followed by drying or solvent removal preferably by means of reduced pressure or vacuum to ensure maximum adsorption and sequestering of the compound in the pores; optionally the support material is dissolved, yielding a solution or an ultra fine suspension of the compound, preferably in association with the lipid; optionally the solution of ultra fine suspension is further processed to obtain a free flowing powder by evaporating the solvent • A method for the preparation of a composition for improving the dissolution and the bioavailability of a biologically active compound having low water solubility wherein,
A biologically active compound having low water solubility and optionally surfactant and/ or a lipid is first finely dispersed or preferably dissolved in a suitable solvent,
The solution or suspension is mixed with a porous support material, followed by drying or solvent removal preferably by means of reduced pressure or vacuum to ensure maximum adsorption and sequestering of the compound in the pores; optionally the support material is dissolved, yielding a solution or an ultra fine suspension of the compound, preferably in association with the lipid; optionally the solution of ultra fine suspension is further processed to obtain a free flowing powder by evaporating the solvent
-A method for the production of any one of the dosage forms as mentioned above, wherein for the preparation of any one of the afore-mentioned compositions
- A therapeutic amount of a biologically active compound having low water solubility and surfactant and optionally a lipid are first finely dispersed or preferably dissolved in a suitable solvent;
- The solution or dispersion is loaded into the pores of a porous support material, preferably by means of reduced pressure or vacuum to ensure maximum adsorption and sequestering of the compound in the pores;
- Optionally the support material is dissolved, yielding a solution or an ultra fine suspension of the compound, preferably in association with the lipid; and
- The composition is further processed by extrusion into granules e.g. for filling in hard gelatine capsules, and/ or compacted into tablets by addition of suitable excipients commonly used in solid dosage forms, such as, for example as anti-caking agents, disintegrants, fillers, adsorptives, pulverizing and moulding excipients.
A detailed description of the components present in the compositions according to the instant invention, the process for the preparation of the composition and its further processing is given below:
Component a)
A biologically active compound having low water solubility is, in particular, any therapeutic agent or a combination of different therapeutic agents of low water solubility, which is suitable in a therapeutically effective amount for the intended mode of administration, e.g. topi- cal, parenteral, e.g. intramuscular in the form of injection dispersions, or oral, e.g. in the form of capsule fillings. A preferred therapeutic agent is sparingly soluble in water and has a solubility in water of less than 500 mg/1000 ml, especially of less than 100 mg/1000 ml. Suitable for topical, parenteral, e.g. intramuscular, or oral administration, e.g. as capsule fillings are sparingly soluble therapeutic agents, e.g. immunosuppressants having a macrolide structure, typically cyclosporin A, cyclosporin G, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, gusperimus, non-steroidal antiphlogistic agents and salts thereof, typically acetylsalicylic acid, ibuprofen or S(+)-ibuprofen, indomethacin, diclofenac (Na and K-salt), piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen, fenoprofen, felbinac, sulindac, etodolac, oxyphenbutazone, phenylbutazone, nabumetone; dihydro- pyridine derivatives having cardiovascular activity, e.g. nifedipine, nitrendipine, nimodipine, nisoldipine, isradipine, felodipine, amlodipine, nilvadipine, lacidipine, benidipine, masnipine, furnidipine, niguldipine; immunodepressants and stimulants, typically a-liponic acid, muramyl peptides, e.g. muramyl dipeptide or muramyl tripeptide, romurtid, alkaloids, e.g. vincopectin, vincristine, vinblastin, reserpine, codeine, ergot alkaloids, typically bromocriptine, dihydroergotamine, dihydroergocristine; CNS acting agents, e.g. carbamazepine, imipra ine, antitumour agents, e.g. chlorambucil, etoposide, teniposide, idoxifen, tallimustin, teloxantron, tirapazamine, carzelesin, dexniguldipine, intoplicin, idarubicin, miltefosin, trofosfamide, teloxantrone, melphalan, lomustine, 4,5-- bis(4Ηuoroanilino)phthalimide; 4,5-dianilinophthalimide; immunomodulators, typically thymoctonan, prezatid copper acetate; H2-receptor antagonists, typically famotidine, cimetidine, ranitidine, roxatidine, nizatidine, omeprazole, proteinkinase inhibitors; or HIV-1 or HIV-2 protease inhibitors or leucotriene antagonists; anticoagulants and antithrombotics.
Instead of being in the form of a free acid or in basic form, the above-mentioned therapeutic agent may be present in the pharmaceutical composition in the form of a pharmaceutically acceptable salt, typically as hydrobromide, hydrochloride, mesylate, acetate, succinate, lac- tate, tartrate, fumarate, sulphate, maleate, and the like. Particularly suitable are corticoids for dermal administration, e.g. halogenated corticoids, e.g. amcinonide, dexamethasone, triamcinolone-16D,27D-acetonide, betamethasone (17-valerate), flumetasone (21-pivalate), flupredniden-21 -acetate, clobetasol-17-propionate, mometasone- 17-(2-furoate), diflorasone-17,21-diacetate, fluocinolone acetonide, clocortolone-21-pivalate or 21-hexanoate, diflucortolone-21-valerate, fludroxycortide, halometasone, fluocinonide, or fluocortinbutyl; or non-halogenated corticoids, e.g. prednisolone, methyl prednisolone ace- ponate, or hydrocortisone or derivatives thereof, e.g. hydrocortisone-17-butyrate or acetate.
These corticoids may also be combined with antimycotic, sulphonamides or estrogen derivatives. Suitable for dermal formulations are also astringents, anti-acne agents, antipsoriasis agents, or antipruritic agents. Particularly suitable for topical administration are topical antibiotics, e.g. tetracyclin, erythromycin, fusidinic acid, framycetine sulphate, neomycin, meclocyclin, gentamycin, leu- comycin, streptomycin, ganefromycin, rifamexil, ramoplanin, spiramycin, clindamycin, ba- citracin, oxytetracyclin, sulphonamides, and other antibacterial and antiviral agents, e.g. po- dophyllotoxin, idoxuridin, heparine, foscarnet, vidarabine, tromantadine, idoxuridine, aci- clovir, antimycotic agents, e.g. nystatin, amphotericin, flucytosine, miconazole, fluconazole, griseofulvine, terbinafine, natamycin, clotrimazole, econazole, miconazole, fenticonazole, o oconazole, bifonazole, oxiconazole, tioconazole, ketoconazole, ciclopiroxalamine, nafti- fine, terbinafine, amorolfine, tolnaftate, or ciclopirox and the corresponding salts thereof. The above-mentioned antibiotics and antimycotic agents may be combined with other corti- costeroids, antibiotics or antimycotic agents.
Preferred as sunscreens for topical administration are active agents such as UV-B filtering substances, e.g. 4-aminobenzoic acid, homosalate, oxybenzon, 3-imidazolyl-4-yl-acrylic acid and derivatives thereof, 2-phenylbenzimidazol-5-sulphonic acid and salts thereof; 2,3- dihydroxypropyl-4-amino-benzoate, 2-ethylhexyl-4-dimethyl-aminobenzoate, ethyl 4-[bis(2- hydroxypropyl)amino]benzoate, 2-ethylhexyl-4-methoxy-cinnamate, 2-ethylhexylsalicylate, ethylpoly(oxyethylene)-4-{bis-[(2-hydroxyethyl)-polyoxyethylene]amino}benzoate, 3-(4- imidazolyl) acrylic acid, isopentyl 4-methoxycinnamate, 4-isopropylbenzyl salicylate, D-(2- oxo-3-bornylidene)-toluene, D-(2-oxo-3-bornylidene)-toluene sulphonic acid, D-(2-oxo-3- bornylidene)-toluene-p-xylene, 2-phenyl-5-benzimidazole sulphonic acid, 3,3,5-trimethyl- cyclohexylsalicylate, N,N,N-triιnethyl-D-(2-oxo-3-bornyUdene)-toluene-p-toluidiniumm.eth- ylsulphate, or octyl triazone, or UV-A filtering substances, e.g. butyl methoxydibenz- oylmethane, isopropyldibenzoylmethane, benzophenone-4, 3, or 10 or Colipa S 71. Suitable sunscreens are listed in Pflegekosmetik: Ein Leitfaden, W.Raab, U.Kindl; Govi-Verlage, D- Frankfurt 1991 and in Ullmann's Encyclopedia of Industrial Cltemistry, VCH Publisliers, Fifth Complete Revised Edition, Volume A 24, Entry Skin Cosmetics.
Particularly suitable for topical administration are also lipophilic vitamins, typically vitamin A (retinol, free acid or derivatives thereof), B (Bl: thiamine, B2: riboflavine, B6: pyrid- oxin, panthenol, pantothenic acid, vitamin B12 and combinations thereof), vitamin C, D, E (tocopherol), biotin or vitamin K; membrane hpids with functional properties, also retinoids and carotinoids, oils with therapeutic, antimicrobial, cosmetic organoleptic properties, such as cumin seed oil, wheat germ oil, shea butter, sebum regulators and sterols, pumpkin oil, borage and evening primrose oils.
The concentration of the therapeutic agent or combination thereof is determined by the known dosage amount to be administered and can be in the range from 1.0 to 30.0% by weight, preferably from 5.0 to 20.0% by weight, more particularly from 5.0 to 12.0% by weight, based on the weight of the carrier composition.
Examples of suitable lipophilic feed additives are astaxanthin, canthaxanthin, zeaxanthin and lutein. Examples of compounds used in nutriceuticals are ubiquinones, sitostanols, sitosterols and antioxidants such as lycopenes, B-carotene, polyphenols, isoflavones.
Examples of lipophilic drugs are immunosuppressants e.g. cyclosporin A, cytostatics e.g. taxol, anti inflammatories e.g. ibuprofen, HIV proteases, antinypertensives e.g. nifedipine, felodipine, photosensitisers e.g. benzoporphyrin, zinc phthalocyanine tin-ethyl purpurine and antibiotics e.g. amphotericin, ny statin, chloramphenicol. Component b)
The support material is selected such that it does not chemically react with the active compound and serves little physiological role other than to maintain and stabilise a hydrophobic compound in dispersion. The primary particles making up the agglomerates are smaller than 1 μ and may be as small as about 0.02 μ. These are held together by physical forces. The size of the agglomerates is in the range between about 2 μ to about 250 μ, with inter-particle channels or pores accounting for specific surface areas between 50m2/ g to 500 m2/g. Because of the very large internal surfaces available for adsorption, the support material is porous and highly absorbent.
According to a preferred embodiment, the invention comprises as component b) a porous particulate support material selected from the group consisting of, for example, amorphous aluminometasilicate, calciumsilicate, silica, including porous silicon dioxide and silicic acid, dibasic anhydrous calcium phosphate and maltodextrin and polystyrene beads/ micro- sponges.
Preferred support materials which are employed in this invention include inorganic solids, e.g. calcium hydrogen phosphate, which is corresponds to the general formula CaHPθ4*mH2O (m: 0 D m D2), particularly support materials commercially available of the type Fujicalin®, and magnesium aluminometasilicate, which corresponds to the general formula Al2O3 ,MgO,2 Si02 ,n H2O (n: 0 C3 n D2), particularly support materials commercially available of the type Neusilin®, calcium silicate, e.g. Ca2SiO4 or Ca3SiO, and dibasic anhydrous calcium phosphate.
In a preferred embodiment of the invention the composition comprises as component b) a porous particulate support material selected from the group consisting of amorphous Al203 «MgO-2SiO2 «nH20, CaHPO4 »mH2O, CaSiO4, CasSiOs and dibasic anhydrous calcium phosphate. Suitable FUJICALIN products are SG and S and characterised by a mean pore size of 7,0 x 10- 10 m, a mean particle size of about 2-10 μ, a specific volume of about 1.5 ml/g or more, a BET specific surface area of 20 m2/g to 60 m2/g, and an oil and water absorption capacity of about 0.7 ml/g. Suitable NEUSILIN products are Grades SI, SGI, UFL2, US2, FH2, FLl, FL2,S2, SG2,NFL2N and NS2N. Particularly preferred grades are S , SGI US2 and UFL2. The most preferred support material for many applications is grade US2. Those materials, which are amorphous, typically have a specific area of about 100 m2/g to about 300 m2/g, an oil absorption capacity of about 1.3 ml/g to about 3.4 ml/g, a mean particle size of about 1 μ to about 2 μ and a spe- cif ic volume of about 2.1 ml/ g to about 12 ml/ g.
Other suitable support materials are precipitated amorphous calcium silicate, e.g. Zeo- pharm® 600 with 300 m2/g, and oil absorption capacity of at least 450 ml/ 100 g, Hubersorb® 250 NF with oil absorbing capacity of 250 - 300 ml/ 100 g and Zeopharm® 80 (precipitated amorphous silica) with 140 m2/g and oil absorption capacity of 185 - 215 ml/ 100 g. amorphous support material, typically have a specific area of about 100 m2/g to about 300 m2/g, an oil absorption capacity of about 1.3 ml/g to about 4.5 ml/g, a mean particle size of from about 1 μ to about 2 - 14 μ and a specific volume of about 2.1 ml/g to about 12 ml/g.
Another organic support material is maltodextrin supplied by Matsutani Chemical industry Co., Ltd. Japan (Pineflow™ Pineflow™ S) which has a specific surface area of 0.36 m2/g. 0.44 m2/ g and oils absorbable capacity of 120 and 160%, respectively.
Alternative organic or inorganic porous materials may be used, as long as they have no deleterious effect on the active compound and present internal surface areas, which are comparably large. The amount of support material depends on the surface area required for sequestering a solution or dispersion of the hydrophobic compound inside the pores and the type of solution employed. Generally, if the surface area provided by the particle agglomerates is in the range of 100 m2/g to 500 m2/g, about 2 g to about 10 g of the support material may be needed for every ml of liquid. However this is only a general guide and the ratio of the two components depends very much on the properties of the compound and processing conditions. Component c)
A suitable membrane lipid from synthetic or natural origin is selected from the group consisting of phospholipids, sphingolipids and glycolipids and mixtures thereof.
Membrane lipids are components of living cells. Suitable membrane lipids are phospholipids, which are the most abundant membrane lipid occurring in nature. They can be uncharged, zwitterionic, negatively or positively charged. Examples of uncharged phospholipids are phosphatidyl choline, phosphatidyl ethanolamine or their mono acyl derivatives, sphingomyelin and cholesterol. Examples of negatively charged membrane lipids are phosphatidyl serrne, phosphatidyl glycerol, phosphatidic acid, phosphatidyl inositol, cerebrocides, glycolipids cardiolipin. The membrane lipids may be derived from natural plant or animal or microbiological sources, synthesised or partially synthesised, including polyethylene glycol (PEG) derived diacyl and monoacyl equivalents. Special fractions of soy lecithins which contain several phosholipid types, their monoacyl- derivatives, non polar lipids and free fatty acids have improved solubilisation potential and low viscosity due to their heterogeneous composition and may be preferred in some cases. Such blends are commercially available, for example, from Lipoid KG. The term membrane lipid of natural origin also comprises membrane Hpids that have been modified by enzymatic action from natural sources.
In a preferred embodiment of the invention the membrane phospholipid of component c) is selected from the group of diacylphosphatidylcholine, monoacylphosphatidylcholine and mixtures thereof.
According to a particularly preferred embodiment of the invention the membrane phospholipid of component c) selected from the group consisting of soybean lecithin, soybean lecithin with about 80%, preferably more than about 90%, monoacylphosphatidylcholine content and enzyme modified soy lipid with about 60%, preferably more than about 70%, monoacylphosphatidylcholine content.
A suitable phospholipid of natural or synthetic origin is represented by the general formula
1 H2C — O - R.
I
R2- 0 - CH o (|),
I I I
3 CH2- 0 - P - 0 - R3 OH wherein Ri is C10-20acyl; R2 is hydrogen or C10-20acyl; R3 is hydrogen, 2-trimethylamino-l- ethyl, 2-amino-l-ethyl, Cl-4alkyl, Cl-5alkyl substituted by carboxy, C2-5alkyl substituted by hydroxy, C2-5alkyl substituted by carboxy and hydroxy, C2-5-alkyl substituted by carboxy and amino, or an inositol group or a glyceryl group, or a salt of such a compound.
Suitable sphingolipids and glycolipids of natural or synthetic origin are represented by the general formula 1 H — R.
2 I
HC R2
3 I H HC OH
6 CH2
7-17 I
(CH,),,
18 I CH3
wherein X represents the ethylene or vinylen group or a bivalent group of the partial formula:
4 ^ H 5 4 ^ 5 or
OH H H Ri is hydroxy, the phosphatidylcholine, the phosphatidylethanolamine group or hydroxy bound as β-glucoside to a mono- or oligosaccharide group or is an oligosaccharide group substituted by N-acetylneuraminic acid groups; and
R2 is C16-30-acyl, C16-30-α-hydroxyacyl or C16-30-ω-hydroxyacyl, which is optionally esterif ied by a linoleic acid group; The nomenclature used for the phospholipids (I) and (II) and the numbering of the carbon atoms (sn-nomenclature, stereospecific numbering) are in accordance with the recommendations made by the IUPAC-IUB Commission on Biochemical Nomenclature (CBN) in Eur. J. of Biochem. 79, 11-21 (1977) "Nomenclature of Lipids".
In a phospholipid (I) Ri and R2 defined as C10-20acyl are preferably straight-chain C10- 20alkanoyl having an even number of carbon atoms and straight-chain C10-20alkenoyl having from one to three double bonds and an even number of carbon atoms.
Straight-chain C10-20alkanoyl Ri and R2 having an even number of carbon atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
Straight-chain C10-20alkenoyl Ri and R2 having from one to three double bonds and an even number of carbon atoms are, for example, 6-cis-, 6-trans-, 9-cis- or 9-trans-dodecenoyl, -tetra- decenoyl, -hexadecenoyl, -octadecenoyl or -icosenoyl, especially 9-cis-octadecenoyl (oleoyl), and also 9,12-cis-octadecadienoyl or 9,12,15-cis-octadecatrienoyl. A phospholipid (1), wherein R3 is 2-trimethylamino-l-ethyl, is referred to by the trivial name lecithin and a phospholipid (I), wherein R3 is 2-amino-l-ethyl, by the trivial name cephalin. Suitable are, for example, naturally occurring cephalin or lecithin, for example cephalin or lecithin from soybeans or chicken eggs having different or identical acyl groups Ri and R2, or mixtures thereof.
The phospholipid (I) may also be of synthetic origin. The expression "synthetic phospholipid" is used to define phospholipids having a uniform composition in respect of Ri and R2. Such synthetic phospholipids are preferably the above-defined lecithins and cephalins, wherein the acyl groups Ri and R2 have a defined structure and are derived from a defined fatty acid having a degree of purity greater than approximately 95%. Ri and R2 may be identical or different and unsaturated or saturated. Preferably, Ri is saturated, for example n-hexadecanoyl, and R2 is unsaturated, for example 9-cis-octadecenoyl (= oleoyl).
The expression "naturally occurring" defines (in definitions) a phospholipid (I) that does not have a uniform composition in respect of Ri and R2. Such natural phospholipids are likewise lecithins and cephalins, wherein the acyl groups Ri and R2 are structurally undefinable and are derived from naturally occurring or enzymatically derived fatty acid mixtures.
The requirement "substantially pure" defines (in definition) a phospholipid (I) having a degree of purity of more than 90% (by weight), preferably more than 95%, which can be demonstrated by means of suitable determination methods, for example by paper chromato- graphy, by thin-layer chromatography, by HPLC or by means of enzymatic colour testing.
In a phospholipid (I), R3 defined as Cl-C4alkyl is, for example, methyl or ethyl. Methyl is preferred.
R3 defined as Cl-5alkyl substituted by carboxy, C2-5alkyl substituted by hydroxy or C2- 5alkyl substituted by carboxy or hydroxy is, for example, 2-hydroxyethyl, 2,3-dihydroxy-n- propyl, carboxymethyl, 1- or 2-carboxyethyl, dicarboxymethyl, 2-carboxy-2-hydroxyethyl or 3-carboxy-2,3-dihydroxy-n-propyl.
R3 defined as C2-5alkyl substituted by carboxy and amino is, for example, 3-amino-3- carboxy-n-propyl or 2-amino-2-carboxy-n-propyl, preferably 2-amino-2-carboxyethyl. A phospholipid (I) having those groups may be in salt form, for example in sodium or potassium salt form.
Phospholipids (I) wherein R3 is the inositol or the glyceryl group are known by the names phosphatidylinositol and phosphatidylglycerol. The acyl radicals in the phospholipids (I) and in the other components are also customarily known by the names given in brackets:
9-cis-Dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (pal- mitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-oc- tadecenoyl (oleoyl), 9-trans-octadecenoyl (elaidoyl), 11-cis-octadecenoyl (vaccenoyl), 9-cis- icosenoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl (stearoyl), n-icosanoyl (arachidoyl), n-docosanoyl (behenoyl), n- tetracosanoyl (lignoceroyl).
A salt of the phospholipid (I) is pharmaceutically acceptable. Salts are defined by the exis- tence of salt-forming groups in the substituent R3 and by the free hydroxy group at the phosphorus atom. The formation of internal salts is also possible. Alkali metal salts, especially the sodium salt, are preferred.
In an especially preferred embodiment of this invention, purified lecithin from soybeans, for example of the LIPOID S 75 type, is used. Phospholipids (I) of natural or synthetic origin, wherein Ri represents C10-20acyl, R2 represents hydrogen and R3 is as defined above, are known under the term lysophospholipids, particularly lysolecithin, wherein Ri represents C10-20acyl, R2 represents hydrogen and R3 represents is 2-trimethylamino-l-ethyl.
The term sphingolipid or glycolipid of synthetic origin defines lipids (II), wherein segments of their molecular structure have been modified chemically, e.g. by hydration, transesterifica- tion, ester cleavage, esterification, substitution and other conventional process steps. The term synthetic lipid also defines lipids (II) which are obtainable by total synthesis.
The term sphingolipid or glycolipid of natural origin defines lipids (II), which have only been submitted to purification processes, e.g. chromatographic separation methods, but have not been submitted to chemical modifications of their molecular structure.
The term sphingolipid or glycolipid comprises lipids, which are defined by terms such as ceramides, sphingomyelines, cerebrosides, or gangliosides. Ceramides and sphingomyelines are classified together under the term sphingolipids, whereas cerebrosides and gangliosides are classified together under the term glycolipids. In a ceramide (II) Ri is hydroxy. Known ceramides are classified as ceramide 1, 2, 3, 4, 5, 6 I and 6 II. The group of ceramides also comprises so-called synthetic questamides, e.g. questamide H, or so-called synthetic pseudo-ceramides, e.g. pseudo-ceramide SLE, and also lipids named ceramax. The method of preparation and the structure of natural and synthetic ceramides and derivatives thereof is known and described in the publications Yeast Derived Ceramides (Technical Bulletin) issued by Gist-Brocades, in the SOFW Journal, 121st year of publication, Volume 5/95, pages 342-348, authors H.TIteis, and S.Gόring, in the SOFW Journal, 121st year of publication, Volume 5/95, pages 228-238, authors S.Watkins et al. and in Ceramides/ Cholesterol/ Free fatty acids containing cosmetics, SOFW Journal, 122nd year of publication, Vol. 4/96, pages 199-204, authors K. De Paepe et al.
The ceramides which primarily occur in human skin are defined according to INCI rules (formerly CTFA) as ceramides 3. In these ceramides 4-hydroxysphinganine (phytosphin- gosin) is, besides 4-sphingenine (sphingosine), the predominating sphingosine base. In a sphingomyeUne (I) Ri is the the phosphatidylcholine or the phosphatidylethanolamine group.
R2 representing C16-, C18- and C24-acyl is preferably n-hexadecanoyl (palmitoyl), n-octa- decanoyl (stearoyl), n-tetracosanoyl (lignocerinoyl), 9-cis-octadecenoyl (oleoyl) or 9-cis- or 12-cis-octadecadienoyl. R2 representing C16-30-hydroxyacyl is preferably α-hydroxy-octadecanoyl or α-hydroxy- tetracosanoyl or a mixture thereof. Relevant to some degree are acid amides in this position formed with C2-10-α-hydroxycarboxylic acids, e.g. hydroxyacetic acid (glycolic acid), 2- hydroxypropionic acid (lactic acid), 2-hydroxysuccinic acid (malic acid), α-hydroxy- phenylacetic acid (mandelic acid) or mixtures thereof. R2 representing C16-30-ω-hydroxyacyl, preferably in the sphingosine base phytosphingosine, is, e.g. 23-octadecanoyloxytricosanoyl or 23-octadecanoyloxy-heptacosanoyl.
In a glycolipid (II) of the cerebroside type Ri represents hydroxy bound as β-glucoside to a mono- or oligosaccharide group which is optionally substituted by N-acetyl.
Representative monosaccharide groups are D-glucosyl and D-galactosyl, as well as N-acetyl- D-glucosamine and N-acetylgalactosamine.
In a glycolipid (II) of the ganglioside-type Ri represents hydroxy, which is also bound as β- glucoside to an oligosaccharide group containing at least three hexosyl groups, which may be substituted by at least one N-Acetylneuraminic acid groups. These lipids are classified as gangliosides. The compounds defined by the formula I are known and have been described in numerous textbooks and other references from biochemistry.
In an alternative embodiment of the invention the membrane lipid as defined above is combined with a pharmaceutically acceptable surfactant. It is to be understood that membrane lipids are regarded and used as biologically active compounds in cosmetic and some applications.
Suitable pharmaceutically acceptable surfactants include cationic, anionic or non-ionic surfactants. A suitable cationic surfactant, is N-benzyl-N,N-dimethyl-N-2-[2-(4-(l,l,3,3-tetramethylbu- tyl)-phenoxy-ethoxy]-ethylammonio chloride, N-benzyl-N,N-dimethyl-N-2-[2-(3-methyl-4- (l,l,3,3-tetramethylbutyl)-phenoxy)-ethoxy]-ethylammonio chloride (methylbenzethonium chloride), n-dodecyltrimethylammonio chloride or bromide, trimethyl-n-tetradecylammonio chloride or bromide, n-hexadecyltrimethylammonio chloride or bromide (cetyltrimethylam- monium chloride or bromide), trimethyl-n-octadecylammonio chloride or bromide, ethyl-n- dodecyldimethylammonio chloride or bromide, ethyldimethyl- n-tetradecylammonio chloride or bromide, ethyl-n- hexadecyltrimethylaπunonio chloride or bromide, ethyldimethyl-n- octadecylammonio chloride or bromide or n-C12-C16alkyl-benzyldimethylammonio chloride or bromide (benzalkonium chloride or bromide). A suitable anionic surfactant is represented by the general formula
[Ra-(O-A)m-]-Z+, wherein Ra represents a saturated or an unsaturated C6-C24hydrocarbon group, A represents C2-C8alkylene, m represents zero or one, B represents the sulphonate or sulphate group and Z+ represents a monovalent cation. Preferred anionic surfactants are sodium or potassium C12-C20alkylsulphate, e.g. sodium or potassium-n-dodecyl, -tetradecyl, -hexadecyl or octadecylsulphate or -sulphonate, or sodium or potassium C12-C20alkylethersulphate, e.g. sodium or potassium-n-dodecyloxyethyl, tet- radecyloxyethyl, hexadecyloxyethyl or octadecyloxysulphate or -sulphonate.
Suitable non-ionic surfactants are selected from the group consisting of polyglycerol esters, polysorbates, mono- and diglycerides of fatty acids, propylene glycol esters, sucrose fatty acid esters and polyoxyethylene derivatives of sorbitan fatty acid esters. These surfactants are well known in the art and are commercially available.
Suitable polyglycerol esters consist of substantially pure polyglycerol fatty acid ester or of a mixture of different polyglycerol fatty acid esters, wherein the polyglycerol chain preferably contains up to and including 10 units of glycerol, which are esterified with 1-10 acid radicals of saturated or unsaturated carboxylic acids having an even number of 8-20 carbon atoms.
Suitable polyglycerol fatty acid esters having a uniformly defined structure are typically di- glycerol monocaprate, diglyceryl monolaurate, diglycerol diisostearate, diglycerol monoi- sostearate, diglycerol tetrastearate (polyglyceryl 2-tetrastearate), triglycerol monooleate (po- lyglyceryl 3-monooleate), triglycerol monolaurate, triglycerol mono stearate (polyglyceryl 3- stearate), triglycerol monoisosterate, hexaglycerol dioleate (polyglycerol 6-dioleate), hexaglycerol distearate (polyglycerol 6-distearate), decaglycerol dioleate (polyglycerol 10- dioleate), decaglycerol tetraoleate (polyglycerol 10-tetraoleate), decaglycerol decaoleate (polyglycerol 10-decaoleate), decaglycerol decastearate (polyglycerol 10-decastearate). The CTFA nomenclature is given within the brackets. These products are commercially available under the registered trade mark Caprol® (trade mark of Karlshamns USA Inc., Columbus Ohio). Specific product names: CAPROL 2G4S, 3GO, 3GS, 6G20, 6G2S, 10G2O, 10G4O, 10G100, 10G10S. Further products are available under the names of DGLC-MC, DGLC-ML, DGLC-DISOS, DGLC-MISOS, TGLC-ML and TGLC-MISOS from Solvay Alkali GmbH, D- 3002 Hannover.
The mixture of different polyglycerol fatty acid esters is specified under names such as decaglycerol monooleate, dioleate, polyglycerol ester of mixed fatty acids, polyglycerol ester of the fatty acids, polyglycerol caprate, cocoate, laurate, lanolinate, isostearate or rizinolate and are commercially available under the registered trade mark Triodan® and Homo- dan®(trade mark of Grindsted Products, Grindsted Denmark), specific product names: TRIODAN 20, 55, R90 and HOMODAN MO; Radiamuls® (trade mark of Petrofina (FINA), Bruxelles Belgium), specific product name: RADIAMULS Poly 2253; under the name CAPROLPGE860 or ET, or under the registered trade mark Plurol®(trade mark of Gattefosse Etablissements, Saint-Priest, France), specific product name: PLUROL Stearique WL1009 or PLUROL Oleique WL1173. Further products are available under the names PGLC-C1010S, PGLC-C0810, PGLC1010/S, PGLC-LT2010, PGLC-LAN0510/S, PGLC-CT2010/90, PGLC- ISOSTUE, PGLC-RUE, PGLC-ISOS0410 from Solvay Alkali GmbH, D- Hannover. The cited polyglycerol fatty acid esters conform to the specifications listed in the Foodchemi- cal Codex FCCIII under "Monographs", p.232 regarding "description", "requirements" and "tests". Applicable are especially the product specifications published by the indicated producers on the data sheets of the specified product, in particular specifications such as mono- ester content, drop point, free glycerol, free fatty acid, iodine value, form, antioxidants, HLB value, properties and stability.
The cited polyglycerol fatty acid esters in particular conform to the requirements of number E475 of the EC food additives directive (EC directive 74/329) as well as the regulation of U.S. FDA Code 21 CFR_172.854.
According to a preferred embodiment of the invention, suitable polyglycerol esters include triglyceryl monostearate, hexaglyceryl distearate, hexaglyceryl monopalimate, hexaglyceryl dipalmitate, decaglyceryl distearate, decaglyceryl monoleate, decaglyceryl dioleate, decaglycerol monopalmitate, decaglycerol dipalmitate, decaglyceryl monostearate, oc- taglycerol monoleate, octaglycerol monostearate and decaglycerol monocaprylate.
Suitable polysorbates include sorbitan fatty acid esters or polyoxyethylene sorbitan fatty acid esters.
Sorbitan fatty acid esters preferably consists of a sorbitan fatty acid ester which is substantially pure, or of a mixture of different sorbitan fatty acid esters, and the sorbitan skeleton is esterified with 1-3 acid radicals of a saturated or unsaturated straight-chain carboxylic acid having an even number of 8-20 carbon atoms. The acid radical of a saturated carboxyHc acid having an even number of 8-20 carbon atoms which esterifies the sorbitan skeleton is preferably straight-chain with 12, 14, 16 and 18 carbon atoms, typically n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
The acid radical of an unsaturated carboxylic acid having an even number of 8-20 carbon atoms is preferably straight-chain with 12, 14, 16 and 18 carbon atoms, typically oleoyl. Suitable sorbitan fatty acid esters are preferably sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan sesquioleate and sorbitan trioleate. These products are commercially available under the registered trade mark Span® (trade mark of Atlas, Wilmington USA), specific product names: SPAN 20, 40, 60, 65, 80 and 85; Arlacel® (trade mark of Atlas), specific product names: ARLACEL 20, 40, 60, 80, 83, 85 and C; Grill® (trade mark of Croda Chemicals Ltd., Cowick HaU, Snaith Goole GB), specific product names: CRILL 1, 3 and 4; Dehymuls® (trade mark of Henkel, Dusseldorf DE), specific product names: DEHYMULS SML, SMO, SMS, SSO; Famodan® (trade mark of Grindsted Products, Grindsted Denmark), specific product names: FAMODAN MS and TS; Capmul® (trade mark of Karlshamns USA Inc., Columbus Ohio), specific product names: CAPMULS and O; Radiasurf® (trade mark of Petrofina (FINA), BruxeUes Belgium), specific product names: RADIASURF7125, 7135, 7145 and 7155.
The above-mentioned partial fatty acid ester of polyoxyethylene sorbitan consists preferably of a substantiaUy pure ester of sorbitan or a mixture of different esters of sorbitan in which the structure of the fatty acid groups and the length of the polyoxyethylene chains may vary. The hydrophiHc sorbitan is preferably etherified by three hydrophilic polyoxyethylene chains and esterified by a hydrophobic fatty acid group. The sorbitan may, however, alternatively be etherified by only one or two polyoxyethylene chains and correspondingly esterified by two or three fatty acid groups. The basic sorbitan structure is altogether substituted by a minimum of two and a maximum of three hydrophiHc groups, the term "hydrophiHc group" embracing the polyoxyethylene chains, whereas the fatty acid groups are hydrophobic.
The polyoxyethylene chain is linear and has preferably from 4 to 10, especiaUy from 4 to 8, ethylene oxide units. The ester groups on the basic sorbitan structure are derived from a saturated or unsaturated, straight-chain carboxyHc acid having an even number of from 8 to 20 carbon atoms. The ester group derived from that carboxyHc acid is preferably straight- chained having 12, 14, 16 or 18 carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n- hexadecanoyl or n-octadecanoyl. The ester group derived from an unsaturated carboxylic acid having an even number of from 8 to 20 carbon atoms is preferably straight-chained having 12, 14, 16 or 18 carbon atoms, for example oleoyl. The mentioned esters of sorbitan are in conformity with the data given in the British Pharmacopoeia (speciaHsed monograph) or Ph.Helv.VII. In particular, the product specifications pubHshed by the mentioned manufacturers with the information on data sheets for the relevant product, especiaUy specifications such as shape, colour, HLB value, viscosity, ascending melting point and solubiHty, apply.
Suitable partial fatty acid esters of polyoxyethylene sorbitan are commercially obtainable under the trademark Tween® of ICI Corp. and known by the chemical names polyoxyethyl- ene(20 or 4)sorbitan monolaurate (TWEEN 20 and 21), polyoxyethylene(20)sorbitan mono- palrrύtate or monostearate (TWEEN 40 and 60), polyoxyethylene(4 or 20)sorbitan mono- stearate or tristearate (TWEEN 61 and 65), polyoxyethylene (20 or 5)sorbitan monooleate (TWEEN 80 or 81) and polyoxyethylene(20)sorbitan trioleate (TWEEN 85).
The cited sorbitan fatty acid esters and the polyglycerol fatty acid esters conform to the specifications Hsted in the British Pharmacopeia (special monography) or in Ph. Helv. VI. Applicable are especially the product specifications pubHshed by the indicated producers on the data sheets of the specified product, in particular specifications regarding e.g. form, colour, HLB value, viscosity, ascending melting point and solubiHty.
According to a preferred embodiment of the invention suitable polysorbates are obtainable from the reaction product of monoglycerides or sorbitan esters with ethylene oxides. Examples of useful polysorbates include polyoxyethylene 20 mono- and diglycerides of saturated fatty acids, polyoxyethylene 4 sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 20 sorbitan monooleate, polyoxyethylene 5 sorbitan monooleate, polyoxyethylene 20, sorbitan trioleate, sorbitan monopal itate, sorbitan monolaurate, propylene glycol monolaurate, glycerol monostearate, diglycerol monostearate, glycerol lac- tyl-palmitate. Another group of suitable surfactants includes, with HLB values provided in brackets, includes decaglycerol monolaurate [15.5]; decaglycerol distearate [10.5]; decaglycerol dioleate [10.5]; decaglycerol dipalmitate [11.0]; decaglycerol monostearate [13.0]; decaglycerol monooleate [13.5]; hexaglycerol monostearate [12.0]; hexaglycerol monooleate [10.5]; hexaglycerol mono-shortening [12.0]; polyoxyethylene (20) sorbitan monolaurate [16.7]; polyoxyethylene (4) sorbitan monolaurate [13.3]; polyoxyethylene (20) sorbitan monopalmi- tate [15.6]; polyoxyethylene (20) sorbitan monostearate [14.9]; polyoxyethylene (20) sorbitan tristearate [10.5]; polyoxyethylene (20) sorbitan monooleate [15.0]; polyoxyethylene (5) sorbitan monooleate [10.0]; polyoxyethylene (20) sorbitan trioleate [11.0]. As is appreciated by those with skiU in the art, the HLB value for a surfactant is an expression of its hydrophiHc-HpophiHc balance, i.e., the balance of the size and strength of the hydrophiHc (polar) and HpophiHc (non-polar) groups of the surfactant.
Lactic acid derivatives include sodium stearoyl lactylate and calcium stearoyl lactylate.
A particularly preferred surfactant is d-Alpha tocopheryl polyethylene glycol 1000 succinate (TPGS)
Also other surfactants or substances with amphipathic character like poloxamers, polyethoxylated castor oil derivatives and protective coUoids like low- and high-molecular-weight components of, for example, gelatin, fish gelatin, starch, dextrin, plant proteins, pectin, gum arabic, casein, caseinate or mixtures of these, the protein-containing protective colloids, in particular non-gelling low-molecular-weight protein hydrolysates and higher-molecular- weight gelling gelatins being preferred. However, poly(vinylalcohol), polyvinylpyrroHdone, methyl cellulose, carboxymethyl ceUulose, hydroxypropyl ceUulose and alginates can also be used. The surfactants suitable for the invention are not limited to the examples provided above. In general, the weight ratio of surfactant to support material is less or equal to 1 : 2, regardless of drug content. Where TPGS is employed as the preferred surfactant, it may be present in excess of the active compound.
Optional components: Component d)
Suitable pharmaceuticaUy acceptable additional excipients are added to the carrier composition in such an amount as to make up 100% by weight together with the amounts of components a), b) and c) as weU as of the therapeutic agent or combination thereof. Additional excipients can be present in the composition in amounts of 0% to c.75% by weight. Additional excipients depend on the choice of the pharmaceutical dosage form. PharmaceuticaHy acceptable diluents are added to Hquid dosage forms, such as drops, suspensions or capsule fillings, typicaUy ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, butylenes glycol , hexalene glycol, or mixture thereof, glycerol or water, or mixtures thereof.
A suitable pharmaceutical diluent is a carrier Hquid, e.g. water, which is optionaHy admixed with a C2-C4-alkanol, especiaUy ethanol, and is present in the composition in the degree of purity necessary for the intended pharmaceutical or cosmetic administration. Hi the event that parenteral administration is intended, water has the degree of purity prescribed for in- jection formulations in accordance with the regulations of the national pharmacopoeias, such as the U.S. Pharmacopoeia (USP) or the Deutsches Arzneibuch (DAB) and is germ- and pyrogenfree. Water is germfree when topical dosage forms or cosmetic uses are intended. The carrier Hquid ethanol is optionaUy admixed as C2-C4-alkanol when parenteral dosage forms are intended. In that event ethanol is present, ethanol has the degree of purity (at least 96%) prescribed for injection formulations. The proportion of ethanol for injection formulations may vary within wide limits from about 1.0% to about 10.0%. For topical dosage forms or cosmetic uses, ethanol, isopropanol or mixtures thereof may be optionaUy admixed as C2- C4-alkanol. The proportion of C2-C4-alkanol for topical formulations or cosmetic uses may vary within wide limits from about 0.1% to about 10.0%, preferably 0.1% to 2.0%. Other suitable excipients are hydrophiHc and HpophiHc polymers which are used as fiUers bulking agents and viscosity improvers. Examples are the natural gums, ceUulose derivatives etc.
Typical additives may be present in the composition, which are characteristic for the intended pharmaceutical dosage form or cosmetic uses. They have a degree of purity in ac- cordance with the regulations of the national pharmacopoeias mentioned above. Depending on the intended use, additives may be water soluble or Hpid soluble. Suitable additives /excipients include those that are useful for the preparation of o/w, w/o, w/o/w emulsions, gels, ointments, creams, oUs, lotions, foams, or sprays. The addition of preserving agents, antioxidants, stabilizers or softening agents is recommended. A preferred additive in topical pharmaceutical and cosmetic compositions is cholesterol or a corresponding salt thereof, e.g. cholesterol sulphate with the purity necessary for the intended cosmetic or pharmaceutical administration.
Suitable additives for pharmaceutical and particularly cosmetic compositions are also free fatty acids derived by conventional ester cleavage from the above-mentioned triglyc- erides (III), surfactants, e.g. anionic, cationic, or amphoteric, gel-forming agents, emulsifiers, e.g. ethoxylated fatty alcohols, hydrogenated ethoxylated castor oUs, partial esters of fatty acids and modified fatty acids with glycerol, polyglycerol, and sorbitol, orthophosphoric acid esters, or siHcone surfactants, HpophiHc constituents, e.g. soHd, semisolid, and Hquid hydrocarbons, natural oUs and waxes, suicone and volatile siHcone oU, guerbet alcohols, fatty acid esters, isostearic acid derivatives, co-emulsifiers, thickeners, gelling agents, foam stabiHzers, fat-restoring substances, pearl-lustre and turbidity agents, preservatives, dyes, colored pigments, perfume oUs, and preferably Ught filters (sunscreens).
Conventional excipients can also be added to oral dosage form, e.g. capsule fillings, e.g. semi-synthetic or synthetic, substantiaUy pure triglyceride or a pharmaceuticaUy acceptable triglyceride of natural origin. A triglyceride of natural origin is preferred, for example groundnut, sesame, sunflower, oHve, maize kernel, soybean, castor, cottonseed, rape, thistle, grapeseed, fish or coconut oU. Other additives, include for example preservatives, typicaUy benzyl alcohol, ethanol, p-hydroxybenzoate, sorbic acid; antioxidants, typically tocopherols, butylhydroxyanisol, butylhydroxytoluene, ascorbic acid, ascorbylpalmitate; stabUisers, typi- cally citric acid, tartaric acid, EDTA, flavourings or fragrances.
Gelatin capsules and the like are suitably fiUed with conventional plasticisers to stabiHse the gelatin sheU. Such excipients are typically sorbitol, sorbitan, polyvinylpyrrolidone, hydroxy propylmethyl cellulose (HPMC), hydroxypropyl ceUulose, methyl ceUulose or colloidal siHcon dioxide. A further object of the invention is to prepare a composition comprising a HpophiHc biologi- caUy active compound with low water solubiHty in molecular association or dispersion in at least one membrane Hpid sequestered in the interior of a porous support material without using organic solvents. This is done by partitioning a HpophiHc compound into an aqueous lipid suspension preferably using a high shear mixer. The compound is intercalated in the HpopMHc domain of the Hpid aggregates which is then loaded into the support material, foUowed by removal of excess water. The compound remains in molecular association with the Hpid and is sequestered in the pores of the support material. Preferably the Hpids used in this case are a mixture of a monoacyl Hpid and diacyl Hpid form natural soy or egg Hpids.
To prepare the composition according to this invention, the HpophiHc compound is first finely dispersed or preferably dissolved in a suitable solvent or solvent mixture , which may include a membrane Hpid and/ or surfactant. In the next step, the solution or lipid suspension is loaded into the pores of the support material, preferably by means of reduced pressure or vacuum to ensure maximum adsorption on the internal surfaces lining the pores after solvent removal. Adequate deposition into the interior spaces of the particle agglomerates may also be obtained by e.g. spray drying and fluidised bed drying. The role of the solvent/ s is to dissolve the compound with low water solubiHty and carry it into the pores of the support material. Preferably the solvent/ solvent mixture employed is a volatile solvent with low viscosity. More preferably a surfactant is also included to reduce surface tension effects, de-aerate the surfaces of the material and aUow maximum penetration into the pores. The method employed enables the compound to be carried into the internal pores of the agglomerates either in solution or in ultra fine form when the solvent is removed. In contrast, solutions and suspensions in viscous Hquids including those using hot melt techniques are less efficient. It is found that when a HpophiHc drug is sequestered within the extensive internal surfaces provided by the pores of a support material using the process described in this invention, the composition yields a highly dispersive solution or an ultra fine suspension of the drug, optionaUy in association with a Hpid/ surfactant, after release from or dissolution of the support material, compared to drug particles on their own. This is Ulustrated in the release profiles shown in Fig 1. The agglomerates have an internal surface area greater than 25 m2/g. The fact that the HpophiHc compound remains in highly dispersive ultra fine precipitate inside the minute pores of the absorbent support material is surprising. It is beUeved that the precipitate may be constrained by the very smaU pore size and stabiHsed in ultra fine possibly amorphous form/s inside the channels. H another embodiment, the HpophiHc drug may remain molecularly dispersed in a second component which is a membrane lipid and/ or surfactant. Depending on the compound, the ultra fine pores of the support material may be sufficient to physicaUy prevent or constrain crystallisation of the drug to larger crystals. Therefore it may only be necessary to make sure that the drug is deposited or absorbed as a solution into the pores of the support material in the first instance. The solvent, with or without the Hpid is removed, leaving behind an adsorbed material. Preferably, primary loading is carried out by firstly impregnating the pores of a blank or unloaded support material with the compound associated in membrane Hpid and/ or surfactant, or dissolved in a solvent alone, which term includes aqueous media and mixtures thereof. The solvent is then removed using any appropriate drying method e.g. spray drying, vacuum, or freeze drying, etc., to obtain a loaded particulate composition. Alternatively, secondary loading may be carried out by firstly preparing a powder blend comprising the unloaded porous support material, compound with low water solubiHty and optionaUy membrane lipid and /or surfactant. In this method, the compound is loaded into the pores of the support medium foUowing addition of a suitable solvent/ solvent mixture. Removal of the solvent may take place in situ from biological surfaces after topical appHcation. The composition obtained may be used as such as a free flowing powder or a Hquid suspension. The composition may also be further processed by extrusion into granules, and compacted into tablets by addition of suitable excipients commonly used in solid dosage forms. Organic and inorganic materials widely used as anti-caking agent, disintegrant, filler, adsorptive, pulverizing and moulding excipient may be used. After oral administration the support material dissolves in the low pH conditions of the upper GI tract to release the compound in ultra fine form or in molecular dispersion.
In one embodiment of the invention, dissolution takes place inside the body after oral administration. The support material dissolves in the GI tract, releasing the HpophUic com- pound from the interior pores of the support material. If the compound is sequestered as a solution in Hpid, transfer into the surrounding medium wiU be instant. Even if it is not, because of the ultra fine form, dissolution wUl be much improved. In another embodiment of the invention, a powder composition comprising the compound sequestered in ultra fine form in a support material may be further processed by contact with acid medium in a suit- able container. By this treatment the support material is dissolved and the HpophUic compound may be harvested or collected as ultra fine powder. The powder has improved solubiHty and dissolution profile and may be processed further into suitable dosage forms.
A further embodiment of the invention relates to a mixture, e. g. a placebo mixture, suitable for the preparation of composition for improving the dispersibiHty of biologicaUy active compounds having low water solubUity, which comprises b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; c) A membrane Hpid; or, in the alternative a membrane Hpid and/ or at least one pharmaceuticaUy or cosmeticaUy acceptable surfactant; and, optionaUy, d) Additional pharmaceuticaUy acceptable excipients.
The mixture defined above comprises compositions, wherein the component b), the porous particulate support material, is present
• In combination with a membrane Hpid, as defined above, or
• In combination with a membrane Hpid and a pharmaceuticaUy or cosmeticaUy acceptable surfactant as defined above; or
• In combination with a pharmaceuticaUy or cosmeticaUy acceptable surfactant as defined above. The presence of additional pharmaceuticaUy or cosmeticaUy acceptable excipients, component d), is optional in any of the embodiments of above.
The mixture comprising the components b), c) and d) is obtainable by applying the above- mentioned methods and is suitable for secondary loading or dispersion of any agent of low water solubiHty, e.g. nutritional agents, vitamins, diagnostic agents or enzyme preparations.
Examples
The invention and its advantages w l become even more apparent from the foUowing examples. The examples serve for Ulustrative purposes only and do not limit the scope of the invention. Example 1
700 mg of a HIV protease inhibitor (MW: 516.2, empirical formula: C20Hi6Br2N6θ solubUity:< 0.010 μg/ml), and 70 mg of TPGS are dissolved by stirring in 105 g of a (25/75) mixture of ethanol 96% and dichloromethane. The solution is added in fractions under stirring to 7 g NEUSILIN Grade US2 (Fuji Chemicals). The addition of the fractions is repeated until complete addition of the solution to NEUSILIN. The solvent mixture is removed under vacuum for 180 min at room temperature after addition of each fraction. The resulting free flowing powder is fiUed into 25 gelatin capsules OO, each containing 300 mg of powder. The capsules are suitable for oral administration. Hi place of NeusiHn, porous maltodextrin (Pineflow™, Matsutani Chemical Industry Ltd) is equaUy suitable. For characterisation purposes, the content of one capsule is added to one Hter of 0.1 M HCl in a dissolution apparatus as described in USP 24. After one hour stirring at 37°C ultra fine particles of HIV protease inhibitor is obtained.
Example 2
In a manner analogous to Example 1, the HIV protease inhibitor is dissolved in a solution of 35 mg TPGS (instead of 70 mg TPGS), and VP 815, an enzyme modified soy Hpid with 60% monoacyl Hpid content (Lipoid KG, Ludwigshafen, FRG).
Example 3
In a manner analogous to Examples 1 and 2, NEUSILIN is replaced with 7 g Zeopharm® 600 (calcium siHcate) (Hubert Inc., Havre de Grace, MD USA). Example 4
1 g cyclosporin A (Refarmed Chemical Ltd. Lugano, CH) is dissolved under stirring in 9.0 g ethanol 90%. The solution is added under stirring to 10 g NEUSILIN Grade US2 (Fuji Chemicals). The alcohol is removed under vacuum for 180 min at room temperature. The resulting free flowing powder is fiUed into 32 gelatin capsules OO, each containing 300 mg of powder. The capsules are suitable for oral administration. For characterisation purposes, the content of one capsule is added to one Hter 0.1 M HCl containing 0.5% sodium dodecyl sulphate in a dissolution apparatus as described in USP 24 to one Hter 0.1 M HCl containing 0.5% sodium dodecyl sulphate. After one hour of stirring at 37° C an ultra fine suspension of cyclosporin particles is obtained.
Example 5 lg cyclosporin A, practicaUy insoluble in water, (Refarmed Chemical Ltd. Lugano, CH) and 100 mg of Soybean lecithin S 75 (Lipoid KG, Ludwigshafen, FRG) are dissolved under stirring in 8.9 g ethanol 96%. The solution is added under stirring to 10 g NEUSILIN Grade US2 (Fuji Chemicals) The alcohol is removed under vacuum for 180 min at room temperature. The resulting free flowing powder is fiUed into 32 gelatin capsules OO, each containing 300 mg of powder. The capsules are suitable for oral administration. For characterisation purposes, the content of one capsule is added to one litre 0.1 M HCl in a dissolution apparatus as described in USP 24. Alter one hour stirring at 37° C an ultra fine dispersion of cyclosporin is obtained.
Example 6 lg cyclosporin A, practicaUy insoluble in water, (Refarmed Chemical Ltd. Lugano, CH) and 3g VP 814 Soybean lecithin with 80% by weight monoacyl lecithin (Lipoid KG, Ludwigshafen, FRG) are dissolved in 6 g ethanol absolute. The Hpid solution is stirred into 10 g NEUSILIN Grade US2 (Fuji Chemicals). The alcohol is removed under vacuum for 180 min at room temperature. The resulting free flowing powder is fiUed into 32 gelatin capsules OO, each containing 300 mg of powder. The capsules are suitable for oral administration. For assessment of dispersibUit , the content of one capsule is added to one litre of 0.1 M HCl in a dissolution apparatus as described in USP 24. After one hour stirring at 37° C an ultra fine suspension of cyclosporine associated in Hpid particles is obtained.
Examples 7-9
Examples 7, 8 and 9 are carried out in a manner similar to Examples 4, 5 and 6, but instead of 10 g Neusilin™, 20 g of Fujicalin® Grade SG from Fuji Chemicals is used. Example 10
400 mg of a peripheral benzodiazepine receptor Hgand (MW: 394.86, empirical formula: C21H19C1N4O2, solubiHty: 1 μg/ml), and 80 mg of TPGS (d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate) are dissolved in 15 g dichloromethane. The resulting solution is loaded in stages to 2 g Neusilin™ Grade US2 from Fuji Chemicals. The solvent is removed under vacuum for 180 min at room temperature after addition of each fraction. This procedure was repeated until aU the solution was impregnated into Neusilin. This is an example based on primary loading as described.
The resulting free flowing powder is fiUed into 6 gelatin capsules OO, each containing 300 mg of powder. The capsules are suitable for oral administration. For characterisation purposes, the content of one capsule is added to one liter of 0.1 M HCl in a dissolution apparatus as described in USP 24. After one hour stirring at 37 ° C a finely dispersed suspension of HIV protease particles is obtained.
Example 11
Siπύlar to Example 10, instead 80 mg TPGS, 40 mg TPGS and VP 815 an enzyme modified soy lipid with 60% monoacyl Hpid content (Lipoid KG, Ludwigshafen, FRG) are used.
Example 12
This example demonstrates the better dispersabUity/ dissolution of a HpophUic compound impregnated into a porous support material compared to drug substance alone. 410 mg of a peripheral benzodiazepine receptor Hgand (M wt: 394.86, empirical formula: C2ιHi9ClN4O2 and water solubiHty: 1 μg/ml) with activity in neuro-degenerative diseases, is dissolved in 15 g dichloromethane. The solution is added in aliquots to 2.1 g NeusUin UFL2 [Fuji Chemicals Industry]. After addition of each portion the solvent is removed by drying in a vacuum oven at room temperature. Example 13
DispersabUity of the loaded composition of Example 12 is compared with the drug alone (particle size <10 μm) at a concentration of 0.1 mg/ml using 900 ml of 10 % w/v sodium dodecyl sulphate and 0.1 M HC in a 1 Htie dissolution beaker (USP XXIV) stirred with a paddle at 50 rpm at 37°C. The amount of drug exposed to the dissolution medium is three times lower than the maximum solubiHty of the drug substance. At regular time intervals aHquots of the incubation media are taken and after fUtration through a 0.45 μm pores size fUter, drug concentration is determined using a specific HPLC method
The dissolution rates of the two samples are iUustrated in Fig 1. It is seen that 96 wt % of the compound with low water solubiHty sequestered inside the pores of the porous support material disperses and dissolves within 6 min. compared to the drug alone which takes 45 min. under very similar conditions to reach the same level of dissolution.
This result clearly demonstrates the improved dispersabUity/ dissolution rate of a HpophUic compound when it is impregnated within the pores of a porous support material.

Claims

Claims
1. A composition for improving the dispersibiHty of biologicaUy active compounds having low water solubiHty, which comprises a) A biologicaUy effective amount of at least one biologicaUy active compound having low water solubiHty; b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; c) At least one membrane Hpid; or, in the alternative, at least one membrane Hpid combined with at least one pharmaceuticaUy acceptable surfactant; and, optionally, d) Additional pharmaceuticaUy acceptable excipients.
2. A pharmaceutical or cosmetic composition according to claim 1 for improving the dispersibiHty of biologicaUy active compounds having low water solubUity, which com- prises a) A therapeuticaUy or cosmeticaUy effective amount of at least one biologicaUy active compound having low water solubUity; b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; c) At least one membrane Hpid; and, optionaUy, d) Additional pharmaceuticaUy acceptable excipients.
3. A pharmaceutical or cosmetic composition for improving the dispersibiHty of biologically active compounds having low water solubiHty, which comprises a) A therapeuticaUy or cosmeticaUy effective amount of at least one biologicaUy active compound having low water solubiHty; b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; c) At least one membrane Hpid combined with at least one pharmaceuticaUy acceptable surfactant; and, optionaUy, d) Additional pharmaceuticaUy acceptable excipients.
4. A composition according to claim 1, which comprises as component b) a porous particulate support material selected from the group consisting of amorphous alumi- nometasiHcate, siHca, calciumsiHcate, dibasic anhydrous calcium phosphate and malto- dextrin.
5. A composition according to claim 1, which comprises as component b) a porous particulate support material selected from the group consisting of amorphous Al203-MgO-2 SiO2 »nH2O, CaHP04 »mH2O, Ca2SiO4, Ca3SiO5 and dibasic anhydrous calcium phosphate.
6. A composition according to claim 1, which comprises as component c) a membrane Hpid of synthetic or natural origin selected from the group of diacylphosphatidylchoHne, monoacylphosphatidylcholine and mixtures thereof of synthetic or natural origin.
7. A composition according to claim 1, which comprises as component c) a membrane Hpid selected from the group consisting of soybean lecithin, soybean lecithin with 80% monoacylphosphatidylcholine content and enzyme modified soy Hpid with 60% monoacylphosphatidylcholine content.
8. A composition according to claim 1, which comprises as component c) a membrane phosphoHpid combined with a non-ionic surfactant selected from the group consisting of tocopherol polyethylene glycol 1000 succinate, poloxamer, polyethoxylated castor oU and a protective coUoid.
9. A mixture suitable for the preparation of composition for improving the dispersibiHty of biologicaUy active compounds having low water solubiHty, which comprises b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; c) A membrane Hpid; or in the alternative at least one membrane lipid and/ or at least on pharmaceuticaUy or cosmeticaUy acceptable surfactant; and, optionaUy, d) Additional pharmaceutically or cosmetically acceptable excipients.
10. A process for the preparation of a pharmaceutical or cosmetic dosage form according to claim 1, which is characterised in that in a suitable solvent or solvent mixture a homogeneous dispersion is prepared, which comprises a) A biologicaUy effective amount of at least one biologicaUy active compound having low water solubiHty; b) A porous particulate support material capable of incorporating within its pores the biologicaUy active compound; and, optionaUy, c) A membrane phosphoHpid; and/ or a pharmaceuticaUy acceptable surfactant; and, d) Additional pharmaceuticaUy acceptable excipients;
And the homogeneous dispersion is converted to a suitable pharmaceutical or cosmetic dosage form f oUowing primary or secondary loading.
11. A method for improving the dispersibiHty of biologicaUy active compounds having low water solubUity, which comprises i) Dissolving or dispersing a biologicaUy effective amount of at least one biologicaUy active compound having low water solubiHty in a suitable volatile pharmaceuticaUy acceptable solvent; u) Dissolving or dispersing in the compound solution at least one membrane phosphoHpid; or, in the alternative, at least one pharmaceuticaUy acceptable surfactant; or mixture of said membrane Hpid and surfactant, optionally, additional pharmaceuticaUy acceptable excipients; and
Hi) Adding the solution or dispersion to a porous particulate support material capable of incorporating within its pores the biologically active compound; foUowed by removal of the solvent, to produce a composition with increased aqueous dispersibiHty of said compound.
12. A method for improving the dispersibiHty of biologically active compounds having low water solubUity, which comprises
Dissolving a biologicaUy effective amount of at least one biologicaUy active compound having low water solubiHty in a suitable volatile pharmaceuticaUy acceptable solvent; Adding the solution to a porous particulate support material capable of incorporating within its pores the biologicaUy active compound; f oUowed by removal of the solvent, to produce a composition with increased aqueous dispersibiHty of said compound and optionaUy other excipients
EP03734705A 2002-01-28 2003-01-28 Composition comprising low water soluble compounds within porous carriers Ceased EP1476137A1 (en)

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EP02250559 2002-01-28
EP02250559 2002-01-28
EP02257932 2002-11-18
EP02257932 2002-11-18
PCT/EP2003/000847 WO2003063835A1 (en) 2002-01-28 2003-01-28 Composition comprising low water soluble compounds within porous carriers
EP03734705A EP1476137A1 (en) 2002-01-28 2003-01-28 Composition comprising low water soluble compounds within porous carriers

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EP1795183B1 (en) * 2005-12-09 2009-07-15 Teva Pharmaceutical Industries, Inc. Aqueous dispersions and solutions of difficult to dissolve compounds and methods of their preparation
CN101346129A (en) * 2005-12-22 2009-01-14 巴斯夫欧洲公司 Method for producing vitamin E-adsorbates
EP2135601A1 (en) * 2008-06-20 2009-12-23 Capsulution Nanoscience AG Stabilization of amorphous drugs using sponge-like carrier matrices
WO2011120530A1 (en) * 2010-03-31 2011-10-06 Lifecycle Phama A/S Porous tablets as carriers for liquid formulations
GB201008043D0 (en) * 2010-05-14 2010-06-30 Unilever Plc Compositions
CN110013467B (en) * 2018-01-10 2021-09-17 上海汉都医药科技有限公司 Solid particle, preparation method thereof and pharmaceutical composition containing solid particle
US20210169854A1 (en) 2019-09-20 2021-06-10 Novartis Ag 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid and its salts formulation
WO2022195545A1 (en) 2021-03-18 2022-09-22 Novartis Ag Novel pharmaceutical formulations

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JPH05238930A (en) * 1992-02-28 1993-09-17 Eisai Co Ltd Long-acting medicine
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