WO2005110360A2

WO2005110360A2 - Compositions for injection

Info

Publication number: WO2005110360A2
Application number: PCT/EP2005/005365
Authority: WO
Inventors: Steve Leigh; Mathew Louis Steven Leigh; Peter Van Hoogevest
Original assignee: Phares Pharmaceutical Research N.V.
Priority date: 2004-05-18
Filing date: 2005-05-17
Publication date: 2005-11-24
Also published as: WO2005110360A3

Abstract

The present invention relates to a homogeneous pharmaceutical composition for the gradual release of biologically active compounds after intramuscular or subcutaneous administration comprising at least one membrane lipid which is in the liquid crystalline state and a process for the preparation of said composition.

Description

Compositions for Injection

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.

In human and veterinary practice, 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. Furthermore, 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.

The preparation of a sustained release injectable formulation containing lipophilic or hydrophilic drugs for intramuscular/ subcutaneous administration poses a challenge. Prior art compositions where the compounds are injected as solutions employing organic solvents and/ or surfactants, or complexing with hydroxy-propyl-beta-cyclodextrin are unsatisfactory. Large amounts of surfactant e.g. polysorbate 80 and polyoxylcastor oil are required to dissolve an adequate amount of a lipophilic drug. The use of large amounts of surfactant results in low tolerability at the site of injection. On dilution with body fluids the compound may precipitate at the injection site and cause local irritation and inflammation. Because of crystal formation, it may not be possible to maintain an effective therapeutic concentration in the systemic circulation. Oily vehicles, such as medium chain triglycerides or soy bean oil are used as alternatives in some cases. However 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. However, 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. Clearly, the claims are restricted to non polymeric materials which precipitate and solidify after injection and therefore the lipid used must be in the solid state (rigid) at the injection site. In sharp contrast, 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.

Summary of the invention:

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 comprising, a) 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.

Preferred 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. Description

In this specification, the following definitions apply: "Biologically 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.

"Viscous Lipid Reservoir " (VLR) describes a gel-like, coherent viscous lipid matrix associated with a biologically active compound, which swells in aqueous fluids and gradually releases the compound or it may disperse into lipid particles associated with the compound.

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. In the first instance following injection from a hypodermic syringe, 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. 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. After the initial hydration period which may last from several minutes to several hours or even weeks, depending on the composition, 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. It is a feature of the invention that 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. Preferably, 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. It is another object of the invention to deliver the lipophilic compound to the body so that the drug is released in a sustained manner and maintain therapeuti- caHy effective blood levels. It is also an object of the invention to entrap hydrophiHc compounds efficiently in the VLRs. The compositions may be used for therapeutic or prophylactic purposes, for instance in vaccination, as sustained release reservoir. Furthermore, the Hquid injectable compositions should be amenable to heat or irradiation sterilisation or sufficiently mobile to allow sterile filtration. Surprisingly, it has been found that 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. However, it is possible that 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.

Unexpectedly, in most cases, 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. In in vitro studies, the HpophiHc compound does not precipitate out on dilution with aqueous fluid and is released gradually in molecular dispersion, from the VLR. However, it is also possible that the HpophiHc compound may be suspended as Hpid associated drug particles, In vivo, 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.

The 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.

H another aspect, 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.

The 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. In case the hydrophiHc compound is not sufficiently soluble or stable in the com- position comprising membrane Hpid and water miscible organic solvent, 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-molekύlen (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. testosteronenanthate, testosteronproprionate, medroyxprogester- oneacetate, testosteroncypionate, levonorgestrel, estradiolvalerate, cyproteronacetate, antineoplasti.es, e.g. methotrexate, antiWstaminics, antiparasitics, insecticide,s e.g tricla- bendazole, albendazole, mebendazole, fenbendazole. ivermectin, methoprene, lufenuron, moranteltartrat, anti-acromegaly drugs like ccteotide, low moleculat weight heparine, e.g. certoparine, nadroparine, enoxaparine, dalteparine, reviparine, thronibmeinhibitors, e.g. hirudine, osteoporosis drugs, e.g. calcitonine und vitaminen, z.B. vitamine B 12 (cyanoco- balamin). 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 These could be could be saturated Hke myristic or lauric acid, or saturated, branched fatty acid residues as described in US patent specifi- cation 5,747,066 mono-unsaturated Hke oleic acid, or poly unsaturated, Hke Hnoleic acid. Also partiaUy hydrogenated natural phosphoHpids can be used. Special fractions of 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. In addition, 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. Examples of 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.

Examples of 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 810™, Miglyol 812™, Miglyol 812 N™, Miglyol 829™, Miglyol 840™ Miglyol 8810™, 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

Other 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,

wherein Ri represents Cio-Caoacyl; R₂ represents hydrogen or Cιo-C.2oacyl; R3 represents hydrogen, 2-tiim.ethylamino-l-ethyl, 2-amino-l-ethyl, Cι-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.

Another preferred embodiment of the present invention relates to the afore mentioned composition which is a pharmaceutical composition 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,

wherein Ri represents Cιo-C2oacyl;

R2 represents hydrogen or Cιo-C₂oacyl;

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

In general the composition 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 μm 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.

The foUowing examples illustrate the invention without Hmiting the scope thereof:

Examples:

1) 70 g of soybean Hpid (70 - 90 % purity ) phosphatidylcholine content with Hquid crystalline to gel state phase transition temperature lower than 0°C; Lucas Meyer (VP 200)) are dissolved under stirring and nitrogen in 20 g ethanol. 10 g of triclabendazole (a HpophiHc anthelmintic drug) are dissolved under stirring in the ethanol phase containing the phosphoHpid. The resulting solution is heated to 60°C and filtered under sterUe conditions through a 0.45 μm pore size filter. 22 ml of the solution is filled into vials under nitrogen and closed with a rubber stopper and aluminium cap to ensure steriHty (i.e. formu- lation HT/ 00/42). In an analogue manner formulation 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.

Composition in w/w % of test formulations

In 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.

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.

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.

4) An intramuscular formulation is prepared in a manner analogous to Example 1 with 60 g soy bean Hpid (Lucas Meyer VP200), 15 g MIGLYOL 810™ and 15 g ethanol as excipients. 5) An intramuscular formulation is prepared in a manner analogous to Example 1 with 55 g soy bean Hpid (Lucas Meyer VP200), 20 g MIGLYOL 810™ and 15 g ethanol as excipients. 6) 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.

7) An intramuscular formulation is prepared in a manner analogous to Example 1 with 10 g albendazole as active agent.

8) H place of VP 200, an alternative containing 70% phosphatidylcholine may also be used in the examples. 9) 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. To this clear solution (11 parts by weight) 6.5 parts by weight of an aqueous solu- tion containing a morpholino oHgonucleotide is added to form a homogeneous gel suitable for s.c. for injection.

10) In the foUowing 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.

Claims

1. A Hquid composition for intramuscular or subcutaneous acbninistration to a Hv- ing organism which hydrates in aqueous fluids and converts to a homogeneous- viscous Hpid matrix after injection enabling the gradual release of a biologicaUy active compound or the conversion of said Hpid matrix into Hpid particles associated with the compound 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 gel to Hquid crystalline phase transition temperature below 40°C c) 5% to 50% 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,

2. A composition according to claim 1 comprising, 15 %to 40% by weight of a biologicaUy active compound, 40% to 70% by weight of membrane Hpid, 5 % to 30% by weight of at least one water miscible organic solvent.

3. A pharmaceutical co[ph3]mposition according to claim 1 containing a biologicaUy active compound with low wa[ph4]ter solubiHty.

4. A composition according to claim 1 which is pr[ph5]epared by mixing the contents of i) a first container comprising at least one membrane Hpid homogeneously dispersed in a pharmaceuticaUy acceptable organic solvent or solvent mixture and, optionaUy, other physiologically acceptable excipients and H) a second container comprising the biologicaUy active compound having high water solubiHty and optionaUy other physiologicaUy acceptable excipients.

5. A pharmaceutical composition according to claim 1 comprising 10% to 95% by weight of phosphoHpid phosphatidylcholine and with a gel to Hquid crystalline phase transition temperature below 40 °C suitable for injection containing at least 40% by weight of a phosphatidylcholine.

6. A pharmaceutical composition according to claim 1 or 2 for use as a subcutaneous or intramuscular formulation in veterinary appHcations.

7. The composition of claims 1 - 8 which is subjected to steriHszation by filtration or heat or irradiation treatment.

8. The composition of any of the preceding claims that is contained in a single or multi dose vial or pre-fiUed syringe.

9. A process for subcutaneous or intramuscular injection which is characterized by a viscous Hpid matrix after injecting a hydratable homogeneous pharmaceutical composition comprising; a) a water-miscible, pharmaceuticaUy acceptable organic solvent, a) a therapeuticaUy effective amount of at least one biologicaUy active compound, b) at least one membrane Hpid suitable for injection purposes, and optionaUy at least one pharmaceuticaUy acceptable carrier Hquid and other additives suitable for injection purposes.

10. A process according to claim 9 which comprises a water miscible, pharmaceuti- caUy acceptable organic solvent selected from the group consisting of 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 (tet- raglycol), isopropanol, lactic acid butyl ester, N-methylpyrroHdone, soUcetol, pro- pylene carbonate, propylene glycol diacetate, tetrahydrofurfuryl alcohol, diethyl- ene glycol mono ethyl ether.