+

WO2005110360A2 - Compositions pour injection - Google Patents

Compositions pour injection Download PDF

Info

Publication number
WO2005110360A2
WO2005110360A2 PCT/EP2005/005365 EP2005005365W WO2005110360A2 WO 2005110360 A2 WO2005110360 A2 WO 2005110360A2 EP 2005005365 W EP2005005365 W EP 2005005365W WO 2005110360 A2 WO2005110360 A2 WO 2005110360A2
Authority
WO
WIPO (PCT)
Prior art keywords
injection
weight
hpid
hquid
active compound
Prior art date
Application number
PCT/EP2005/005365
Other languages
English (en)
Other versions
WO2005110360A3 (fr
Inventor
Steve Leigh
Mathew Louis Steven Leigh
Peter Van Hoogevest
Original Assignee
Phares Pharmaceutical Research N.V.
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 N.V. filed Critical Phares Pharmaceutical Research N.V.
Publication of WO2005110360A2 publication Critical patent/WO2005110360A2/fr
Publication of WO2005110360A3 publication Critical patent/WO2005110360A3/fr

Links

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases

Definitions

  • compositions for Injection are provided.
  • the present invention relates to membrane lipid compositions for injection in human or veterinary practice. It particularly relates to compositions containing at least one mem- brane lipid which is in the liquid crystalline state at body temperature, a biologically active agent, a water miscible organic solvent.
  • the compositions hydrate in body fluids after intramuscular or subcutaneous injection and convert to viscous lipid reservoirs at the injection site that gradually release the biologically active compound into the surrounding systemic circulation over a period of several hours or weeks.
  • intramuscular and subcutaneous injections are often necessary to administer drugs. This is especially the case when the drugs are not absorbed after oral administration or emergency medication is needed (An Introduction to Veterinary Pharmacology, Ed. Churchill Livingstone, Edinburgh 1976, p3.). Injection allows more predictable bioavailability and therapeutic effect.
  • a depot injection is the preferred vehicle for sustained delivery of drugs having a very short biological half life. This is especially true for hydrophilic drugs e.g. proteins.
  • the slow and extended release properties of depot formulations are more acceptable to patients because fewer injections are required. Therefore, there is a need for safe and efficient parenteral formulations of hydrophilic as well as lipophilic compounds which release the biologically active component over a period of several hours or longer.
  • Oily vehicles such as medium chain triglycerides or soy bean oil are used as alternatives in some cases.
  • most lipo- philic compounds are poorly soluble in oils, and repeated administration of oily vehicles may cause side effects.
  • Aqueous or oily suspensions are alternative options for intramuscular injection of Hpophilic compounds. Requirement for aseptic processing and the difficulties of terminal end sterilisation make these formulations uneconomic.
  • Polylac- tic(glycolic)acid (PLGA) microparticles (Conti, B., J. Microencapsulation, 1992, 9(2) 153 - 166) of Hpophilic drugs is yet another approach claimed for depot injections which release the active compound over a period of months. These particles are difficult to manufacture because of the need for large amounts of ecologically damaging solvents and lyophilisa- tion, and the attendant risks of burst effects, etc.
  • Sustained delivery technology that may be suitable for hydrophilic compounds is limited to PLGA microparticles or specifically for insulin, to aqueous suspensions prepared form insoluble amorphous or crystalline Zn2+ protein complexes.
  • Water-in-oil formulations of vaccines have been used in veterinary medicine, for sustained release of antigens.
  • Liposomes have frequently been mentioned in the literature as sustained delivery formulations, particularly for hydrophilic drugs.
  • poor entrapment, complex and costly production methods and the necessity for lyophilisation to preserve stability severely restrict the suitability of liposomes as sustained delivery vehicles for general use.
  • EP-A- 0 158 441 relates to pro-liposome compositions based on membrane lipids, to a method of making lipid vesicles by the addition of aqueous fluid to these compositions, and to aqueous dispersions of vesicles.
  • the compositions contain water-soluble, or oil- soluble biologically active compounds. They may also contain an organic solvent, such as ethanol.
  • the compositions are not described for use as sustained release injectables per se for lipophilic or hydrophilic compounds after intramuscular or subcutaneous administration.
  • the present invention is a further improvement of the pro-liposome principle.
  • US patent specification 5,888,533 describes non-polymeric sustained release delivery sys- tem.
  • the invention relates to a method and composition for forming a solid implant by precipitation or coagulation in-situ within the body using non-polymeric materials and an organic solvent that at least partially dissolves the non-polymeric materials.
  • the non- polymeric material is selected from phospholipids, lysoderivatives of phospholipids, sphingornyelins, derivatives of sphingosine, sphingornyelins, ceramides, glycosphingolip- ids, lanolin, lanolin alcohols, and mixtures thereof.
  • the present invention comprises defined membrane lipids and components that hydrate or form homogeneous viscous lipid reservoirs which maintain a mobile, gel-like, liquid crystalline state (fluid) at physiological temperatures around 37 °C.
  • the invention describes:
  • a liquid or gel-like composition for intramuscular or subcutaneous administration to a living organism which hydrates in aqueous fluids and converts to a homogeneous viscous lipid matrix after injection enabling the gradual release of a biologically active compound or the conversion of said lipid matrix into lipid particles associated with the compound
  • a therapeutically effective amount of at least one biologically active compound b) 10% to 95% by weight or more of a membrane lipid suitable for injection pur- poses, with a gel to liquid crystalline phase transition temperature below 40 °C c) 5% to 50% by weight of at least one water miscible, pharmaceutically acceptable organic solvent and optionally, d) a pharmaceutically acceptable carrier liquid suitable for injection purposes and optionally, e) other additives suitable for injection purposes.
  • compositions for injection comprise: a) 15 %to 40% by weight of a biologically active compound, b) 40% to 70% by weight of membrane lipid, c) 5 % to 30 % by weight of at least one water miscible organic solvent.
  • a process for subcutaneous or intramuscular injection which is characterized by a viscous lipid matrix after injecting a hydratable homogeneous pharmaceutical composition comprising; a) a water- iscible, pharmaceutically acceptable organic solvent, a) a therapeutically effective amount of at least one biologically active compound, b) at least one membrane lipid suitable for injection purposes and optionally at least one pharmaceutically acceptable carrier liquid and other additives suitable for injection purposes.
  • Bioly active compound is any substance, inorganic or organic, with a physiological or pharmacological effect.
  • Compound with 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 l'OOO to lO'OOO) as defined in United States Pharmacopoia 24. They are also referred to as lipophilic or hydrophobic compounds.
  • “Compound with high water solubility” means any compound that require 10 or less then 10 parts of water to dissolve 1 part of the compound. They are also referred to as hydrophilic compounds
  • Membrane lipid is the phospholipid or glycolipid component of a biological cell membrane "Sustained delivery" means maintaining a therapeutically effective amount of the administered dose of the compound in the systemic blood or lymph circulation over a period of several hours to weeks .
  • Liquid crystalline state describes the fluidity of membrane lipids above their gel to liquid crystalline phase transition temperature (Tc) where the hydrocarbon tails are freely movable and not rigid.
  • VLR Vehicle Lipid Reservoir
  • the present invention relates to membrane lipid compositions for injection. It particularly relates to compositions containing at least one membrane lipid which is in the liquid crystalline state at physiological temperatures, a biologically active agent, a water miscible organic solvent and optionally other pharmaceutically acceptable excipients.
  • the liquid or flowable membrane lipid composition hydrates in the surrounding body fluids in situ and converts to a ho- mogeneous viscous lipid reservoir (VLR) at the injection site.
  • VLR viscous lipid reservoir
  • the compound is maintained in solution or it may be associated within the lipid matrix as particles which diffuse gradually in a sustained manner into the surrounding tissues before entering the systemic circulation.
  • the bulk VLR may disperse more gradually into smaller drug associated lipid particles (reservoirs) which sustain gradual release of the compound into the systemic circulation.
  • An object of the invention is to offer cost effective, industrially applicable sustained release compositions for a broad range of biologically active compounds. There is no need for complex manufacturing procedures such as emulsification and lyophilisation steps. Stability problems related to aqueous dispersions of membrane lipids such as liposomes are avoided. Membrane lipids which remain in the liquid crystalline i.e. fluid state at physiological temperature are advantageous because the lipids do not undergo a precipitation and solidification process with change of surface and release characteristics which may influence the release profile of the entrapped drug. The liquid crystalline lipids form VLRs at the injection site, which are viscous compositions and can be removed if necessary, by suction with a syringe.
  • the injectable membrane lipid composition hydrates slowly in situ at the site of injection and forms a viscous paste or gel-like composition which does not solidify.
  • the VLR remains coher- ent for at least six hours, and in some cases depending on the composition, for periods of up to one week or longer.
  • It is a further object of the invention to prevent uncontrolled crystallisation of lipophilic biologically active substances which are solubilised or associated in the VLRs.
  • compositions may be used for therapeutic or prophylactic purposes, for instance in vaccination, as sustained release reservoir.
  • Hquid injectable compositions should be amenable to heat or irradiation sterilisation or sufficiently mobile to allow sterile filtration.
  • particular compositions containing between 10% and 95 % or more by weight of at least one membrane Hpid which is in the Hquid crystalline state at physiological temperatures and a suitable water miscible organic solvent or combination of solvents thereof suitable for injection show a sustained release pattern for HpophiHc as weH as hydrophiHc compounds. After intramuscular or subcutaneous injec- tion, the composition hydrates and forms a reservoir for both HpophiHc and hydrophiHc compounds.
  • the compound is present as amorphous drug particles suspended in the homogeneous VLR.
  • the preferred membrane Hpid is naturaUy occurring or synthetic phosphatidylcholine or fractionated lecithins, which contain at least 40% of phosphatidylcholine with a gel to Hquid crystalline phase transition temperature below 40°C.
  • the preferred hydrophiHc solvent to render the composition sufficiently mobile for extrusion from a syringe is ethanol, preferably present at not more than about 30% w/w of the total composition.
  • a simple mixture of an appropriate membrane Hpid and a minor amount of hydrophiHc solvent i.e. no more than 5% w/w is all that is needed to mobiHse the composition and solubiHse HpophiHc compounds or entrap hydrophiHc compound for sustained deHvery at the injection site.
  • the hydrophiHc solvent or mixtures thereof may be almost entirely replaced by an amount of water for injection, provided that the composition is a mobile and has the potential or capacity to further hydrate to a homogeneous viscous Hpid reservoir for the sustained release of the drug.
  • the compositions are ideaHy suited for direct intramuscular or subcutaneous injection in human or veterinary practice.
  • the HpophiHc compound does not precipitate out on dilution with aqueous fluid and is released gradually in molecular dispersion, from the VLR.
  • the HpophiHc compound may be suspended as Hpid associated drug particles.
  • the composition provides a constant and sustained release of HpophiHc as weU as hydrophiHc compound into the systemic circulation without causing undue irritation and discomfort after injection as borne out by studies.
  • the present invention covers sterile injectable compositions in the form of low viscosity, flowable Hquid, suitable for deHvery from a syringe.
  • the compositions are sufficiently free flowing and may be injected using a hypodermic needle.
  • the compositions contain at least one dissolved or Hpid associated HpophiHc or hydrophiHc compound. Where the hydro- phiHc compound is not soluble or stable, it may be added as an aqueous solution to the composition shortly before injection. Preferably the compound is lyophiHsed for storage.
  • the invention is particularly suitable for direct intra-muscular and subcutaneous injection to humans and animals.
  • the composition remains in situ as a VLR that does not rapidly disperse into Hpid particles in body fluids.
  • compositions are fined into single or multi-dose vials, or pre-fiLled syringes, comprising; a) a therapeuticaUy effective amount of at least one biologicaUy active compound b) 10% to 95% by weight or more of a membrane Hpid suitable for injection purposes, with a Hquid crystalline to gel state phase transition temperature below 40°C c) 1% to 50% by weight of at least one water miscible, pharmaceutically acceptable organic solvent and optionaUy d) a pharmaceuticaUy acceptable carrier Hquid suitable for injection purposes and optionaUy, e) other additives suitable for injection purposes.
  • the invention also describes a process for the preparation of Hquid or semi-soHd gel like composition for intramuscular or subcutaneous administration comprising, a) a therapeuticaUy effective amount of at least one biologicaUy active compound, b) 10% to 95% by weight or more of a membrane Hpid suitable for injection purposes, with a Hquid crystalline to gel state phase transition temperature below 40°C c) 1% to 50% by weight of at least one water miscible, pharmaceuticaUy acceptable organic solvent and optionaUy, d) a pharmaceuticaUy acceptable carrier Hquid suitable for injection purposes and optionaUy, e) other additives suitable for injection purposes.
  • compositions are dispensed into single or multi-dose vials or pre packed unit dose syringes and rendered sterile by filtration, heat or irradiation treatment before or after filling.
  • the hydrophiHc compound can be present in a second container, optionaUy in lyophiHsed form.
  • the pharmaceutical composition is preferably injected subcutaneously, which means injection under the skin, or intramuscularly, which means directly into a muscle.
  • Other ad- ministration routes that are possible are, tra-abdominal, intraperitoneal, intraarticular, intracardial, intracoronaral, intradermal, interdental, intercostal, interlobal, interspinal, intracisternal, intralesional, intraductal, intradural, intrapleural, intrathecal, intralumbal, intrauterin, intraperitoneal, intravascular, intraventricular, intratumoral, intraepitheHae, intrafusal, intragluteal, intrahepatic, intracranial, intracerebral, intralymphatical, in- tramammal, intrameduUar, intrasternal und intrathecal .
  • BiologicaUy active substances that are suitable for sustained deHvery, either for human or veterinary appHcations are, DNA-Fragments, immunoglobuHns, interleukins, e.g. IL 1 - IL 11 , immunomodulators, e.g. Alpha-, Beta- Gamma-interferons, cyclosporin, antibodies, cytokines, peptide hormones (antagonists, agonists), e.g.
  • leuproline leuproHde-acetate, busereline-acetate, gosereline-acetate, triptoreHne, LHRH, ACTH, tetracosactide, amorphous and crystaUine insuHn, antigens, growthfactors, e.g. human growthhormone, erythropoetine, fUgrastim, lenograstim, nucleases, enzymea, tumorsuppressionsgenes, aromataseinhibitors, e.g.. Formestan, Antidotes, zB. deferoxamine, antisense-molek ⁇ len (oHgonulceotides), antibiotics, e.g.
  • peniciUin G benzathine, ceftriaxon-disodium, ben- zylpeniciUine, procaine, gentamycine, terramycine, oxytetracycHne, anaesthetics, e.g. methadone, morphine, fentanyl, antirheumatics, e.g. aurothioglucose, Cox-2 inhibitors, tranquiUizers, cardiovascular drugs, corticosteroids, e.g.
  • triamcinolone-diacetate triamci- nolonhexacetonide
  • bethamethasoneacetate methylprednisolone-acetat
  • cortisone-acetate dexamethasonacetate
  • betamethasondiproprionate prednisolonetebuate
  • neuroleptics e.g.
  • fluoxetine clozapine, methylphenidate-HCl, fluspirilene, risperidone, zuclopenthixolace- tate, zuclopenthixoldecanoate, flupentixoldecanoate, fluphenazinedecanoate, per- phenazindecanoate, nadrolonephenpropionate, haloperidoldecanoate, bromocriptine, steroidhormones, e.g.
  • Membrane Hpids are components of aU Hving ceUs. PhosphoHpids axe the most abundant membrane Hpid occurring in nature.
  • Examples of phosphoHpids are, phosphatidyl cho- line, phosphatidyl serine, phosphatidyl glycerol, phosphatidic acid, phosphatidyl inositol, phosphatidyl ethanolamine or their mono acyl derivatives.
  • Other examples of membrane Hpids are cardioHpin, spingomyelin, cerebrocides, glycoHpids and ceramides.
  • the mem- brane Hpids may be derived from natural plant or animal or microbiological sources, syn- thesised or partiaUy synthesised, including polyethylene glycol (PEG) derived diacyl and monoacyl equivalents.
  • the fatty acid composition of these Hpids is such that the Hpids are in the Hquid crystalline state below 40 °C
  • partiaUy hydrogenated natural phosphoHpids can be used.
  • soya lecithins which contain several phoshoHpid types, their monoacyl-derivatives, non polar Hpids and free fatty acids have improved solubiHsation potential and low viscosity due to their heterogeneous composition and may be preferred in some cases.
  • Such blends are commerciaUy avaUable from Lipoid AG, Ludwigshafen, FRG.
  • mixtures with cholesterol or other membrane sterols can be used with the proviso that the mixture has a phase transition temperature lower than 40 °C.
  • water miscible, pharmaceuticaUy acceptable solvents are: ethanol, 96% ethanol, absolute glycerol, propylene glycol, ethyl lactate, polyethylene glycol 300, polyethylene glycol 400, 1,3 butandiol, succinic acid diethyl ester, triethyl citrate, dibutyl sebacate, dimethyl acetamide, DMSO, glycerineformal, glycofurol (tetraglycol), isopropanol, lactic acid butyl ester, N-methylpyrroHdone, soUcetol, propylene carbonate, propylene glycol diacetate, tetrahydrofurfuryl alcohol, diethylene glycol mono ethyl ether .
  • the solvents may be used on their own or in mixtures thereof.
  • a pharmaceuticaUy acceptable carrier Hquid suitable for injection purposes are, water for injection (e.g according to the United States Pharmacopoeia), benzyl alcohol, benzyl benzoate, triglycerides, medium chain triglycerides Hke Miglyol 810TM, Miglyol 812TM, Miglyol 812 NTM, Miglyol 829TM, Miglyol 840TM Miglyol 8810TM, isopropyl myristate, isopropyl palmitate, ethyl oleate, (2-octyl dodecanol), laurinsaure hexyl ester, oleic acid, ricinus on, sesame oU, soybean oU.
  • the volume ratio of water and HpophiHc carrier Hquid when used in the formulations may vary from 0:50 w/w to 50:0 w/w
  • additives suitable for injection purposes are anti-oxidants like alpha tocopherol acetate, ascorbyl palmitate and anti-microbial preservatives Hke methyl paraben and butyl paraben.
  • a preferred embodiment of the invention relates to a Hquid or extrudable composition which converts in the body in the first instance, into a viscous matrix that is a reservoir for the sustained deHvery of a biologicaUy active compound, comprising a) 0.1% to 40% by weight or a therapeuticaUy effective amount of at least one biologicaUy active component with low water solubiHty; b) 10% to 95% by weight or more, preferably 20% to 80%, most preferably 40% to 70% of phosphoHpid or lecithin suitable for injection purposes containing at least 40% by weight phosphatidylcholine and one or more phosphoHpid with the structure,
  • Ri represents Cio-Caoacyl
  • R 2 represents hydrogen or C ⁇ o-C.2oacyl
  • R3 represents hydrogen, 2-tiim.ethylamino-l-ethyl, 2-amino-l-ethyl, C ⁇ -C4alkyl, Ci-Csalkyl substituted by carboxy, C2-Csalkyl substituted by carboxy and hydroxy, C ⁇ -Csalkyl substi- tuted by carboxy and amino, an inositol group or a glyceryl group or a salt of such compound with gel to Hquid crystalline phase transition temperatures lower than 40 °C; c) 1% to 50% by weight, preferably 5% to 30% of at least one water miscible, pharmaceuticaUy acceptable organic solvent, and optionaUy d) a pharmaceuticaUy acceptable carrier Hquid suitable for injection purposes and optionaUy, e) other additives suitable for injection purposes.
  • compositions for intramuscular or subcutaneous administration comprising. a) 0.1% to 40% by weight or a therapeuticaUy effective amount of at least one biologicaUy active component with high water solubiHty; b) 10% to 95% by weight or more, preferably 20% to 80% by weight, most preferably 40% to 70% by weight of phosphoHpid or lecithin suitable for injection purposes containing at least 40% by weight phosphatidylcholine and one or more phosphoHpid with the structure,
  • Ri represents C ⁇ o-C2oacyl
  • R2 represents hydrogen or C ⁇ o-C 2 oacyl
  • R3 represents hydrogen, 2-trimemylamino-l-ethyl, 2-amino-l-ethyl, Ci-Csalkyl substituted by carboxy, C2-Csalkyl substituted by carboxy and hydroxy, C ⁇ -CsaUcyl substituted by carboxy and amino, an inositol group or a glyceryl group or a salt of such com- pound with gel to Hquid crystalline phase transition temperatures lower than 40°C; c) 1% to 50% by weight, preferably 5% to 30% by weight of at least one water miscible, pharmaceuticaUy acceptable organic solvent, and optionaUy d) a pharmaceutically acceptable carrier Hquid suitable for injection purposes, and optionaUy, e) other additives suitable for injection purposes
  • compositions are prepared by dissolving the membrane Hpid(s) in the water miscible organic solvent or solvent mixture at elevated temperature (50 - 60 °C), addition of and dissolving of the HpophiHc component and optionaUy other pharmaceuticaUy acceptable carrier Hquid and other additives at elevated temperature (50 - 60 °C).
  • the com- position is sterUe fUtered through a 0.45 ⁇ m pore size filter, fiUed in vials which are closed with a suitable rubber stopper and sealed with a aluminum cap.
  • compositions containing hydrophiHc compounds are prepared in a similar manner. HydrophiHc components are dissolved in the water miscible organic solvent containing the membrane Hpid and a smaU amount of water for injection to form a homogeneous Hquid composition substantially free from precipitated Hpid particles. Too much water causes precipitation of Hpid particles and is to be avoided.
  • HT/0043 and HT/ 00/44 are prepared.
  • the compositions of the test formulations are summarised in the Table. Twenty ml of the contents of the vials containing the test formulation its are removed from the vial with a 20 ml syringe of Becton Dickinson, equipped with a 14 G needle and were injected subcutaneously at a dose of 10 mg/kg into a cow of 200 kg.
  • Fig. 1 the sustained release properties of these compositions are iUustrated. More specifically, Fig. 1 illustrates Plasma triclabendazole levels obtained after a single s.c injection to a cow of various membrane Hpid containing formulations. Plasma concentration of triclabendazole is depicted in ng/ml. The oral formulation (an aqueous suspension of triclabendazole) is administered at the same dose as the subcutaneous formulations. Fig. 1 shows clearly that the triclabendazole is released over an extended period of time of 20 days.
  • Example 2 An intramuscular formulation is prepared in a manner analogous to Example 1.
  • the phosphoHpid/ ethanol 70/20 w/w mixture is replaced with a 70/20 w/w phosphol- ipid/ ethyUactate mixture.
  • Example 3 An intramuscular formulation is prepared in a manner analogous to Example 1.
  • the phosphoHpid/ ethanol 70/20 w/w mixture is replaced with a 40/40/10 w/w/w phosphoHpid/ ethyl-oleate/ ethanol mixture.
  • An intramuscular formulation is prepared in a manner analogous to Example 1 with 60 g soy bean Hpid (Lucas Meyer VP200), 15 g MIGLYOL 810TM and 15 g ethanol as excipients.
  • An intramuscular formulation is prepared in a manner analogous to Example 1 with 55 g soy bean Hpid (Lucas Meyer VP200), 20 g MIGLYOL 810TM and 15 g ethanol as excipients.
  • An intramuscular formulation is prepared in a manner analogous to Example 1 with 55 g soy bean Hpid (Lucas Meyer VP200), 20 g ethyl oleate and 15 g ethanol as excipients.
  • Example 7 An intramuscular formulation is prepared in a manner analogous to Example 1 with 10 g albendazole as active agent.
  • H place of VP 200 an alternative containing 70% phosphatidylcholine may also be used in the examples.
  • a subcutaneous formulation containing a water soluble oHgonucleotide is prepared as foUows.
  • Six parts by weight of phosphoHpids (5.97 weight parts of VP 80 or VP 200 Soy Bean phosphoHpids of Lipoid KG and 0.03 parts of Egg-PG also of Lucas Meyer) are dissolved in 2.4 weight parts of ethanol, to which 2.6 weight parts of glycerol were added.
  • a formulation suitable for subcutaneous injection having sustained release properties for the water soluble iron chelator desferrioxamine is prepared by in-situ mixing of 1) 77.4 parts by weight of the solution in one container containing 220 mM desferrioxamine, 50 mM imidazole with pH 7.4 with 2) 22.6 parts by weight of the solution of another containing fifteen parts by weight of phosphoHpids (VP 75 Soy Bean phosphoHpids of Lipoid KG) dissolved in 5 parts by weight of ethanol, to which 2.6 parts by weight of glycerol are added. Both solutions are mixed in one single addition by vigor- ously shaking by hand to yield an isotonic solution.
  • 0.5 ml of this mixture is administered subcutaneously to a mouse. Sustained release plasma levels of the desferrioxamine are found for 168 hours. The aqueous solution of desferrioxamine shows only presence of the iron-chelator in plasma for 30 rnin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique homogène destinée à la libération progressive de composés biologiquement actifs après une administration intramusculaire ou sous-cutanée, et renfermant au moins un lipide membranaire sous forme cristalline liquide. L'invention concerne également un procédé de préparation de cette composition.
PCT/EP2005/005365 2004-05-18 2005-05-17 Compositions pour injection WO2005110360A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04252942 2004-05-18
EP04252942.0 2004-05-18

Publications (2)

Publication Number Publication Date
WO2005110360A2 true WO2005110360A2 (fr) 2005-11-24
WO2005110360A3 WO2005110360A3 (fr) 2006-04-06

Family

ID=35394648

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/005365 WO2005110360A2 (fr) 2004-05-18 2005-05-17 Compositions pour injection

Country Status (1)

Country Link
WO (1) WO2005110360A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140086740A (ko) 2012-12-28 2014-07-08 주식회사 종근당 음이온성 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물
US9526787B2 (en) 2011-08-30 2016-12-27 Chong Kun Dang Pharmaceutical Corp. Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same
US9937164B2 (en) 2012-07-26 2018-04-10 Camurus Ab Opioid formulations
US12161640B2 (en) 2012-07-26 2024-12-10 Camurus Ab Opioid formulations

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0753661B2 (ja) * 1984-03-08 1995-06-07 フアレス フアーマスーチカル リサーチ エヌブイ プロ―リポソーム組成物及びリポソームの水性分散物を作る方法
AU688782B2 (en) * 1993-09-30 1998-03-19 Wyeth Rapamycin formulations for oral administration
GB2326337A (en) * 1997-06-20 1998-12-23 Phares Pharma Holland Homogeneous lipid compositions for drug delivery
DE69917609T2 (de) * 1998-03-05 2005-06-09 Phares Pharmaceutical Research N.V., Curaçao Arzneimittel und deren verwendung

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9526787B2 (en) 2011-08-30 2016-12-27 Chong Kun Dang Pharmaceutical Corp. Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same
US9937164B2 (en) 2012-07-26 2018-04-10 Camurus Ab Opioid formulations
US10912772B2 (en) 2012-07-26 2021-02-09 Camurus Ab Opioid formulations
US11110084B2 (en) 2012-07-26 2021-09-07 Camurus Ab Opioid formulations
US11135215B2 (en) 2012-07-26 2021-10-05 Camurus Ab Opioid formulations
US12161640B2 (en) 2012-07-26 2024-12-10 Camurus Ab Opioid formulations
KR20140086740A (ko) 2012-12-28 2014-07-08 주식회사 종근당 음이온성 약리학적 활성물질의 서방성 지질 초기제제 및 이를 포함하는 약제학적 조성물

Also Published As

Publication number Publication date
WO2005110360A3 (fr) 2006-04-06

Similar Documents

Publication Publication Date Title
US10206876B2 (en) Depot formulations of a local anesthetic and methods for preparation thereof
KR101225257B1 (ko) 유동성 데포 제제
EP2750667B1 (fr) Pré-concentré lipidique à libération modifiée d'une substance pharmacologiquement active et composition pharmaceutique la comprenant
RU2649810C2 (ru) Липидный предконцентрат катионного фармакологически активного вещества с длительным высвобождением и содержащая его фармацевтическая композиция
KR20120027298A (ko) 약물 로드된 에멀젼의 제조 방법
JP2013536805A (ja) 難溶性薬物の液体組成物及びその調製方法
KR20070001876A (ko) 주사가능한 지속된 약물 전달 비히클로서의 계면활성제계겔
HUP0301921A2 (hu) Elnyújtott hatóanyag-leadású készítmények hidrofil vegyületek parenterális adagolására
IE62194B1 (en) Lipid formulation systems
CN110381975A (zh) 一种硼替佐米药物组合物及其应用
US20170367978A1 (en) Aqueous topical drug formulation with controlled release and increased stability
PT1317254E (pt) Disperção de partículas de libertação prolongadaa
CN109010255B (zh) 阿片样物质制剂
CN1055483A (zh) 肽药物的长效脂质体制剂及其制备
CN101014319A (zh) 液体贮库制剂
TW200922552A (en) Novel taxoid-based compositions
WO2005110360A2 (fr) Compositions pour injection
CN111012734A (zh) 一种载药网状原位相变凝胶缓释系统及其制备方法
EP4173614A1 (fr) Composition injectable comprenant des dérivés de gnrh
CN111035613A (zh) 一种包含氟维司群的可注射的药物组合物及其制备方法
KR100426636B1 (ko) 주사 가능한 젤 상의 조성물 및 그의 제조방법
CN1895262A (zh) 表阿霉素注射用乳剂及制备方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载