WO1994012154A1 - Formulation contenant des lipides et son procede de preparation - Google Patents

Formulation contenant des lipides et son procede de preparation Download PDF

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Publication number
WO1994012154A1
WO1994012154A1 PCT/GB1993/002393 GB9302393W WO9412154A1 WO 1994012154 A1 WO1994012154 A1 WO 1994012154A1 GB 9302393 W GB9302393 W GB 9302393W WO 9412154 A1 WO9412154 A1 WO 9412154A1
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WIPO (PCT)
Prior art keywords
acid
lipid
formulation
anhydride
substance
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
PCT/GB1993/002393
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English (en)
Inventor
Roger Randal Charles New
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.)
Cortecs Ltd
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Cortecs Ltd
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Filing date
Publication date
Application filed by Cortecs Ltd filed Critical Cortecs Ltd
Priority to AU55314/94A priority Critical patent/AU5531494A/en
Publication of WO1994012154A1 publication Critical patent/WO1994012154A1/fr
Anticipated expiration legal-status Critical
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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1277—Preparation processes; Proliposomes

Definitions

  • the present invention relates to lipid-containing formulations and to the preparation of these formulations.
  • the invention relates to formulations of active substances which are poorly soluble both in water and in organic solvents and, in particular, liposome formulations of these active substances.
  • Liposomes provide a convenient means for the in vivo delivery of active agents, such as pharmaceuticals or nutritional substances.
  • active agents such as pharmaceuticals or nutritional substances.
  • the various processes conventionally used for their preparation involve, as a first step, the dispersion or dissolution of lipid material in a solvent optionally together with the active agent (s).
  • a solvent optionally together with the active agent (s).
  • one method described by Batzri and Korn in Biochim. Biophys . Acta 298 1015 (1973) comprises the solubilisation of lipids in ethanol, followed by the addition of the resulting solution to a large volume of water.
  • a second method (Hauser and Gains, Pro . Natl . Acad.
  • a major problem encountered in these and other known processes for liposo e preparation is that the active agent which it is desired to encapsulate in the liposomes is frequently found to be insoluble in conventional solvents (organic or aqueous) such as are used to disperse or dissolve the constituent lipids. This limits the range of active agents which can be administered by means of liposomes.
  • Conventional solvents, such as chloroform also have the disadvantage of being toxic and yet difficult to remove completely from the liposomes which are produced.
  • a process for the preparation of a lipid-containing formulation comprising co- dissolving an amphipathic lipid and an active agent in a liquid organic acid or a liquid organic acid anhydride; and subsequently neutralising or removing the organic acid or anhydride.
  • amphipathic lipid will depend on the type of product formulation which is required.
  • the formulation may be in the form of liposomes, in which case, at least one amphipathic liposome-forming liquid must be present.
  • amphipathic, liposome-forming lipids include phospholipids, including phosphatidic acid, phosphatidyl cholines (PC's), sphingomyelin, phosphatidyl glycerol, phosphatidyl inositol, phosphatidyl serine, cardiolipin, and natural lecithins such as those derived from egg yolk or soya bean extract.
  • phospholipids including phosphatidic acid, phosphatidyl cholines (PC's), sphingomyelin, phosphatidyl glycerol, phosphatidyl inositol, phosphatidyl serine, cardiolipin, and natural lecithins such as those derived from egg yolk or soya bean extract.
  • PC's phosphatidyl cholines
  • sphingomyelin phosphatidyl glycerol
  • phosphatidyl inositol
  • the formulation may be a lipid suspension in aqueous solution, for example an emulsion or a micellar dispersion.
  • a third possibility is that the formulation is a lipid-water gel.
  • the liposome-forming amphipathic lipids listed above may be included in such formulations but, alternatively, amphipathic non-liposome forming lipids can be used.
  • amphipathic, non-liposome-forming lipids examples include cholesterol and esters and derivatives thereof including other steroids such as ergosterol, fatty acids
  • the active agent must be soluble in the organic acid or anhydride and may be a pharmaceutical, a nutritional substance, an immunological agent, a cosmetic substance, an agrochemical, a biocide or a substance for inclusion in a paint composition.
  • the method is suitable for all active agents, including those which can be conventionally formulated, in liposomes or otherwise, ' it is particularly suitable for active agents which are insoluble or sparingly soluble in conventional organic or inorganic solvents.
  • the active substance will insoluble or sparingly soluble in solvents such as water, halogenated or non-halogenated alkanes, alcohols, cyclic ethers such as tetrahydrofuran (THF) or dioxane, carbonyl or thiocarbonyl containing solvents such as dimethyl- sulphoxide (DMSO) and dimethylformamide (DMF) and aromatic solvents such as pyridine.
  • solvents such as water, halogenated or non-halogenated alkanes, alcohols, cyclic ethers such as tetrahydrofuran (THF) or dioxane, carbonyl or thiocarbonyl containing solvents such as dimethyl- sulphoxide (DMSO) and dimethylformamide (DMF) and aromatic solvents such as pyridine.
  • benzimidazoles for examplealbendazole (methyl-5-propylthio-lH-benzimidazol- 2-yl-carbamate)
  • polyene antibiotics such as amphotericin B
  • carotenoids proteins and peptides for example peptide hormones such as insulin
  • antigens and polyamino acid conjugates include pharmaceutical substances such as benzimidazoles, for examplealbendazole (methyl-5-propylthio-lH-benzimidazol- 2-yl-carbamate)
  • Albendazole is a benzimidazole pharmaceutical used in the treatment of systemic and intestinal infection by helminths, for example in the treatment of hydatid disease. It is difficult to achieve effective blood concentrations of albendazole either by direct intravenous injection, because of the drugs limited solubility, or by oral administration, because of its poor penetration of the gut. In addition, it has, so far, been difficult to administer albendazole in a liposome formulation because of the limited solubility of the drug in conventional aqueous and organic solvents. However, the method of the present invention now makes a liposome formulation of albendazole possible.
  • organic acid refers to a compound having a melting point not greater than 100°C and containing at least one carbon atom and at least one acid moiety.
  • Acid moieties are well known to those skilled in the art and examples include carboxylic (C0 2 H) , phosphoric (PO(OH)) 2 , phosphinic (P(OH) 2 ), sulphonic (S0 3 H) and sulphinic (SO,H) acids.
  • organic acid anhydride refers to the anhydride of an organic acid as defined above.
  • the organic acid is substantially anhydrous to avoid hydrolysis of the lipids and this is particularly important when the amphipathic lipid is cholesterol or a derivative thereof.
  • water is present in the acid it is preferably present at no more than 10% by weight, more preferably no more than 5% by weight and even more preferably no more than 1% by weight. Most preferably the acid should be as dry as possible and contain no more than 0.1% by weight of water.
  • the acid may suitably be dried over zeolitic molecular sieves. The acid is used in an amount sufficient to dissolve the active ingredient.
  • Preferred acids for use in the invention are mono- or di- carboxylic acids.
  • the organic acid may contain from 1 to 20 carbon atoms, although acids having from 1 to 10 carbon atoms are preferred and most preferably, the acid has from 1 to 4 carbon atoms.
  • the carbon chain may be either substituted or unsubstituted and suitable substituents include halogen, particularly chlorine or fluorine, and hydroxyl groups.
  • suitable substituents include halogen, particularly chlorine or fluorine, and hydroxyl groups.
  • carboxylic acids are particularly suitable for use in the present invention and the carboxylic acid may be one whose alkali metal salts are soluble in water, particularly if a liposome suspension is to be formed.
  • an acid having poorly water-soluble salts for example with alkaline earth metals.
  • suitable organic acids include monocarboxylic acids, such as glacial acetic acid and formic acid, although formic acid is less preferred because it cannot be obtained very dry and because it tends to act as a reducing agent towards the lipid material.
  • Derivatives and longer chain homologues of these monocarboxylic acids are also suitable; examples include longer chain acids, homologues such as propionic acid, butyric acid and isobutyric acid, derivatives of monocarboxylic acids, such as trichloroacetic acid, trifluoroacetic acid and phenyl acetic acid, hydroxylated derivatives of monocarboxylic acids such as glycolic acid and D,L-lactic acid and 4-hydroxybutyric acid.
  • Dicarboxylic acids and derivatives thereof, such as glutaric acid and malic acid are also suitable for use in the process of the present invention.
  • an acid anhydride when used, this should be a liquid and be readily hydrolysable. Suitable examples include maleic anhydride and citraconic anhydride.
  • the organic solvent or anhydride is in liquid form so that it can act as a solvent for the amphipathic lipid and the active agent. Therefore, the process will be conducted at a temperature of the melting point of the organic acid or anhydride if it is not liquid at room temperature (20 to 25°). However, elevated temperatures which would be deleterious to the active agent and/or the lipid over the course of the dissolution step should be avoided and, therefore, the dissolution step will preferably be conducted at not more than 100°C. More preferably, the dissolution temperature will be up to 90°C and, most preferably, up to 60°C.
  • the active agent and any lipids may be added to the organic acid or anhydride simultaneously or sequentially, and, if necessary, heated to form the requisite solution.
  • the solution formed by co-dissolution step may be a clear solution or it may, instead, include dispersed lipid material present in its own saturated solution.
  • the organic acid used is, as already briefly mentioned, usually necessary for the organic acid used to be substantially free of traces of water.
  • the cholesterol and phospholipid are co-dried from solution in an organic solvent, for example onto the surface of a vessel, and the organic acid then added.
  • dissolution of cholesterol and esters and derivatives thereof is also helped by warming the acid to about 60°C.
  • the acid or anhydride may either be partially or completely neutralised or, alternatively, may be removed, for example by lyophilisation.
  • Neutralisation is typically achieved by the addition of a basic substance so that the final pH ranges from acidic to slightly alkaline, typically in the range from pH 5 to 8, preferably pH from 5 to 7.
  • the particular pH chosen depends upon the stability of the active agent and of the lipid formulation.
  • a final pH of greater than about 9 prejudices the integrity of liposomes and a slightly acidic pH is preferred for liposomal formulations.
  • the basic substance may be an aqueous alkaline solution of, for example, a hydroxide or a carbonate of an alkali metal or an alkaline earth metal or ammonium.
  • Aqueous sodium hydroxide and ammonium hydroxide are examples of suitable alkaline solutions.
  • Solid hydroxides or carbonates of alkali metals or alkaline earth metals may also be used, as may ammonium carbonate.
  • a preferred example of a solid carbonate is finely divided sodium carbonate decahydrate (Na 2 C0 3 .10H 2 O) . Addition of the basic substance may, if required, be followed by dialysis to remove the salt which forms uoon neutralisation.
  • the choice of base may determine the physical form of the lipid formulation obtained.
  • the acid is one which forms soluble alkali metal salts
  • use of an alkali metal hydroxide or ammonium hydroxide will lead to the formation of liposomes.
  • an alkaline earth metal base is used to neutralise an acid which has poorly soluble alkaline earth metal salts, a gel will be formed.
  • the pH is controlled either by using a standard pH electrode or, particularly when the process is conducted on a small scale, by adding a suitable indicator to the alkaline solution and monitoring the colour change.
  • a suitable indicator is one example of a suitable indicator.
  • the neutralisation step will be monitored to avoid accidental addition of excess base resulting in undesirably high final pH.
  • the organic acid is removed without there usually being the need for subsequent treatment to neutralise the acid.
  • the solution of lipid and active agent in organic acid may suitably be hydrated in aqueous solution.
  • the formulation may be exposed to other conventional procedures either before or after dialysis, or after lyophilisation, to alter the size characteristics of liposomes or to break up non-liposomal particles for instance.
  • Such procedures include sonication, microfluidisation and membrane extrusion.
  • Formulations prepared according to the process of the invention and containing active substances which are insoluble in conventional solvents are also new and, therefore, in a second aspect of the invention there is provided a formulation comprising an active substance which is insoluble or sparingly soluble in organic or aqueous solvents and which is obtainable by a process according to the first aspect.
  • the formulation of the invention may also include other ingredients, for example additional lipids may be present to modify the form or size or physical properties of the lipid-containing domains of the formulations.
  • additional lipids may be present to modify the form or size or physical properties of the lipid-containing domains of the formulations.
  • further types of lipid include non-polar lipids and lipids containing polar or hydrophilic head groups which include functional groups such as phosphate, phosphonate, sulphate, carboxyl, amino pyridinium, hydroxyl or sulphydryl groups.
  • Preferred amphipathic lipids and active agents are as mentioned above for the first aspect.
  • a particularly preferred type of active agent is a benzimidazol such as albendazole.
  • Such formulations are particularly useful in the treatment of systemic and intestinal infection by helminths, for example in the treatment of hydatid disease.
  • the weight ratio of lipid to albendazole may range from 99:1 to 1:99, for example from 75:25 to 25:75 or from 60:40 to 40:60. A ratio from 5:1 to 1:1, especially 3:1, is preferred.
  • Liposomes are formed with a lipid:albendazole weight ratio of from 2:1 to 99:1.
  • Lipid complexes are formed with a lipid:albendazole weight ratio of from 2:1 to 1:99. Ratios for formulations containing other active agents will generally be similar to the above.
  • a method of medical treatment which comprises administering to a host suffering from or exposed to the risk of, systemic or intestinal infection by helminths, for example hydatid disease, an effective non-toxic dose of a lipid-containing formulation comprising a lipid material and albendazole.
  • the formulation is typically administered orally, in an amount which provides a conventional pharmaceutically effective dosage, typically about lOmg per kg body weight, of albendazole per day.
  • the formulation may be a lipid suspension in an aqueous solution or a lipid-water gel, but it is preferred the formulation takes the form of liposomes.
  • Formulations produced in accordance with the invention may be formulated for administration by any route, for example in suspension or as a gel suitable for oral, intravenous or topical administration. Depending on the intended application, they are typically formulated for administration together with one or more pharmaceutically or cosmetically acceptable carriers or diluents.
  • the carriers and diluents will be selected according to the route of administration.
  • the carriers and diluents may be liquids or solids and the lipid-containing formulations may be formulated as a solution, suspension or mixture.
  • the carrier or diluent will generally be a sterile, pyrogen-free liquid, preferably water for injection.
  • the carrier or diluent may optionally include accessory ingredients such as preservatives, anti-oxidants, flavouring agents, colouring agents, suspending agents, buffers and isotonic agents.
  • the carrier or diluent will be a suitable solvent, cream or lotion base and the formulation may further comprise optional accessory ingredients such as preservatives, antioxidants, suspending agents, and buffers.
  • administration to a host of the lipid- containing formulation thus produced may provide a means of increasing the bioavailability of that particular active agent as compared with conventional means of administration.
  • Egg phosphatidyl choline (Lucas Meyer Ovothin 200, 20mg) was dissolved in glacial acetic acid (200 ⁇ l) at room temperature, with shaking. Albendazole (up to lOmg) was then dissolved in the resulting solution.
  • sodium hydroxide (2M, 1.6ml) was introduced, with mixing, to yield a fluid milky suspension.
  • the pH of the resulting suspension was monitored using xylenol blue as indicator, and found to be close to neutrality.
  • Egg phosphatidyl choline (Lucas Meyer Ovothin 200, 20mg) was dissolved in anhydrous glacial acetic acid (20 ⁇ l) in a glass round-bottomed test tube. Cholesterol, which is insoluble in glacial acetic acid alone, (lOmg) was added to the solution and mixed well until it dissolved.
  • Ovothin 200, 25mg was dissolved in the resulting solution.
  • Liposomes containing albendazole prepared as described in Example 1 and sonicated briefly to give a non- sedimenting suspension, were administered orally to a group of rats at a dose of 0.lmg/animal. The same dosage of free albendazole was administered orally to a group of control rats. Blood concentrations were measured at intervals.
  • results show significant differences in the blood concentrations of the chief metabolite albendazole sulphoxide as between the two groups of rats, indicating that the in vivo delivery of albendazole via liposomes increases the bioavailability of the drug.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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Abstract

Un procédé de préparation d'une formulation pharmaceutique d'une substance active qui est insoluble dans les solvants classiques, consiste à codissoudre la substance active et un lipide amphipathique dans un acide organique ou dans un anhydride d'acide et ensuite à enlever ou à neutraliser l'acide ou l'anhydride d'acide. Les formulations obtenues peuvent être liposomiques ou elles peuvent prendre la forme de suspensions de lipides dans une solution aqueuse ou encore de gels lipide - eau. Des substances actives comme l'albendazole, qui sont très peu solubles dans des solvants classiques, conviennent particulièrement bien à une formulation par le procédé de l'invention.
PCT/GB1993/002393 1992-11-23 1993-11-22 Formulation contenant des lipides et son procede de preparation Ceased WO1994012154A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55314/94A AU5531494A (en) 1992-11-23 1993-11-22 Lipid containing formulation and method for its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929224502A GB9224502D0 (en) 1992-11-23 1992-11-23 Method of preparing a lipid-containing formulation
GB9224502.6 1992-11-23

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WO1994012154A1 true WO1994012154A1 (fr) 1994-06-09

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4420727A1 (de) * 1994-06-15 1995-12-21 Rovi Gmbh Hautfreundliche wäßrige Liposomendispersionen, enthaltend alpha-Hydroxycarbonsäuren und/oder alpha-Hydroxyketosäuren in ihrer Salzform
WO1998000169A1 (fr) * 1996-07-02 1998-01-08 Cortecs (Uk) Limited) Preparations hydrophobes contenant des monoglycerides de chaine moyenne
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
CN105232465A (zh) * 2015-11-11 2016-01-13 郑州后羿制药有限公司 一种芬苯达唑脂质体制剂及其制备方法
CN113616798A (zh) * 2021-09-06 2021-11-09 天津农学院 一种甲苯咪唑脂质复合物、制备方法和应用
CN115429756A (zh) * 2021-11-05 2022-12-06 烟台药物研究所 一种阿苯达唑脂质复合物及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2566663A1 (fr) * 1984-07-02 1986-01-03 Ts Lab Helimintologia Vermicide a base de mebendazole et procede pour la preparation de ce vermicide
EP0211647A1 (fr) * 1985-08-07 1987-02-25 Smithkline Beecham Corporation Procédé et composition pour la préparation de liposomes
WO1991002517A1 (fr) * 1989-08-23 1991-03-07 The University Of Nottingham Procede de preparation d'une emulsion d'huile en eau d'un medicament
EP0467838A2 (fr) * 1990-07-17 1992-01-22 Ciba-Geigy Ag Procédé de préparation d'une dispersion des liposomes injectable

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2566663A1 (fr) * 1984-07-02 1986-01-03 Ts Lab Helimintologia Vermicide a base de mebendazole et procede pour la preparation de ce vermicide
EP0211647A1 (fr) * 1985-08-07 1987-02-25 Smithkline Beecham Corporation Procédé et composition pour la préparation de liposomes
WO1991002517A1 (fr) * 1989-08-23 1991-03-07 The University Of Nottingham Procede de preparation d'une emulsion d'huile en eau d'un medicament
EP0467838A2 (fr) * 1990-07-17 1992-01-22 Ciba-Geigy Ag Procédé de préparation d'une dispersion des liposomes injectable

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4420727A1 (de) * 1994-06-15 1995-12-21 Rovi Gmbh Hautfreundliche wäßrige Liposomendispersionen, enthaltend alpha-Hydroxycarbonsäuren und/oder alpha-Hydroxyketosäuren in ihrer Salzform
WO1998000169A1 (fr) * 1996-07-02 1998-01-08 Cortecs (Uk) Limited) Preparations hydrophobes contenant des monoglycerides de chaine moyenne
US6258377B1 (en) 1996-07-02 2001-07-10 Provalis Uk Limited Hydrophobic preparations containing medium chain monoglycerides
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6660286B1 (en) 1997-01-07 2003-12-09 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6667048B1 (en) 1997-01-07 2003-12-23 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US6982282B2 (en) 1997-01-07 2006-01-03 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
US7030155B2 (en) 1998-06-05 2006-04-18 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
CN105232465A (zh) * 2015-11-11 2016-01-13 郑州后羿制药有限公司 一种芬苯达唑脂质体制剂及其制备方法
CN113616798A (zh) * 2021-09-06 2021-11-09 天津农学院 一种甲苯咪唑脂质复合物、制备方法和应用
CN115429756A (zh) * 2021-11-05 2022-12-06 烟台药物研究所 一种阿苯达唑脂质复合物及其制备方法和应用

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Publication number Publication date
AU5531494A (en) 1994-06-22
GB9224502D0 (en) 1993-01-13

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