WO1997048381A1 - Pharmazeutische zubereitung in form von liposomen - Google Patents
Pharmazeutische zubereitung in form von liposomen Download PDFInfo
- Publication number
- WO1997048381A1 WO1997048381A1 PCT/EP1997/003108 EP9703108W WO9748381A1 WO 1997048381 A1 WO1997048381 A1 WO 1997048381A1 EP 9703108 W EP9703108 W EP 9703108W WO 9748381 A1 WO9748381 A1 WO 9748381A1
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- WO
- WIPO (PCT)
- Prior art keywords
- acid
- use according
- liposomes
- lipid
- drug
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- 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—Liposomes
Definitions
- the present invention relates to a pharmaceutical preparation in the form of liposomes, suitable for the solubilization of poorly soluble drugs, in particular of poorly soluble neurokinin antagonists, such as.
- B (+) - camphor-3-carbonyl- (2S, 4R) -4-hydroxypyrolyl (2S) -2-naphthylalanyl- (2-methoxyphenyl) piperazide [BIIC 1996 BS] or 1-methylindol-3-yl-carbonyl - [4 (R) - hydrxoy] -L-prolyl- [3- (2-naphthyl)] - L-alanine-N-benzyl-N-methylamide [FK 888],
- Liposomes are generally understood to be spherical structures - with a diameter of 25 nm to several ⁇ m - from one or more concentric lipid bilayers with an aqueous interior.
- Such lipid vesicles can be produced by finely mechanical distribution of phospholipids (e.g. lecithin) in aqueous media. They are not only used as membrane models in biochemistry or molecular biology, but can also be used as carriers for drugs.
- liposomes Numerous active substances are known from the prior art which are enclosed in liposomes or adsorbed on liposomes. Such liposomal systems are always preferred when the active ingredient is to be released over a longer period of time, undesired drug effects are to be reduced, the active ingredient is to be stabilized or liposomes are to be used as carrier-selective drug vehicles [P. Tyle and B.P. Ram, Targeted Therapeutic Systems, Marcel Dekker Inc., New York, 1990; G. Gregoriadis, Liposome Technology Vol. III, Targeted Drug Delvery and Biological Interaction, CRC Press Inc., Boca Raton, 1984]. Sufficiently water-soluble drugs have mostly been included in the above-mentioned liposomes [M.J.
- the aspect of drug solubilization by liposomes has recently become increasingly important.
- the legalities of liposomal drug inclusion have so far remained relatively unexplored.
- the aim of drug solubilization in general is to To have drug in a mostly aqueous formulation in a molecularly disperse distribution. This formulation can then be administered by the known routes of application.
- Drug preparations solubilized by liposomes should meet the following criteria:
- the drug should be included in the liposome bilayer in molecularly dispersed form, provided that the ratio of the included drug to the amount of lipid used is as high as possible.
- the drug liposomes should have a drug and size stability adapted to the intended use.
- sterile liposome preparations for example by disinfection filtration with membrane filters with a pore diameter of 0.2 ⁇ m.
- Small liposomes, i.e. ⁇ 200 nm liposome diameter should be aimed for in order to maintain sufficient stability of the liposomes during mechanical agitation. This is necessary, for example, when atomizing aqueous liposome preparations using pneumatic nozzle atomizers for inhalation application.
- auxiliaries are to be used as solubilizers.
- the liposome components presented by way of example are suitable as constituents of the body, among other things, because they are non-toxic on the one hand and well tolerated on the other hand, and are broken down by the body without leaving any residue.
- the object of the present invention is now to provide a drug formulation based on liposomes for the solubilization of poorly soluble drugs, in particular for neurokinin (tachykinin) antagonists, as described in the general formula, the preferred areas and in the exemplary embodiments of WO 95/30687 to be disclosed.
- poorly soluble drugs in particular for neurokinin (tachykinin) antagonists, as described in the general formula, the preferred areas and in the exemplary embodiments of WO 95/30687 to be disclosed.
- a primary object of the present invention is to provide a drug formulation based on liposomes for the solubilization of the active ingredients (+) -campher-3-carbo ⁇ yl- (2S, 4R) -4-hydroxyprolyl- (2S) -2- naphthylalanyl- (2-methoxyphenyl) p ⁇ peraz ⁇ d [BIIC 1996 BS] and 1-methyl ⁇ ndol-3-yl-carbonyl- [4 (R) -hydrxoy] -L-prolyl- [3- (2-naphthyl)] - L-alan ⁇ n -N-benzyl-N-methylamide [FK 888] (see Ann Drug Data Rep 15 (1993) 252).
- corticoids - such as flunisolide hemihydrate or beclomethasone dipropionate - can also be used to liposomally include compounds with the invention
- BIIC 1996 is a non-selective neurokinin antagonist, which binds to the NK-
- liposome compositions according to the invention are distinguished, inter alia, by the fact that liposome-forming, amphiphilic auxiliaries, the physicochemical character of the hydrophilic molecular part of which is determined by glycerol or inositol, are particularly suitable for large amounts of poorly soluble medicinal substances - in particular the neurokine antagonists BIIC already mentioned 1996 BS and FK 888 - to be enclosed in liposomes
- the liposome-forming auxiliaries correspond to the general formulas I and II in FIG. 1, in which R ⁇ and R2 in both general formulas independently of one another have a branched or unbranched alkyl radical of a natural, semisynthetically or fully synthetically producible fatty acid - saturated or unsaturated character Have 1 to 30 carbon atoms
- saturated, unbranched fatty acids are formic acid, acetic acid, propionic acid, butyric acid, valenic acid, capronic acid, onanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, maric acid, stearic acid, stanic acid, paladic acid, palmitic acid, palmitic acid, palmitic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid, pentadic acid,
- monounsaturated, unbranched fatty acids examples include acrylic acid, crotonic acid, palmitoleic acid, oleic acid, erucic acid
- Sorbic and linoleic acids are examples of double-saturated, unbranched fatty acids
- triple-saturated unbranched fatty acids are linolenic and elaosteen acids
- Arachidonic acid and clupanodonic acid are examples of a four- and five-fold unsaturated, unbranched fatty acid
- Docosahexaenoic acid is an example of a six-fold unsaturated unbranched fatty acid
- Phosphatidyl glycerols and phosphatidyl ion soles in the form of the free acids or their salts - in particular in the form of the alkali salts - are preferably used, and the sodium salts are very particularly preferably used
- phosphatidylglycerols are particularly preferably used
- DMPG-Na dimystoylphosphatidylglycerol
- DPPG-Na dipalmitoylphosphatidylglycerol
- DSPG-Na distearoylphosphatidylglycerol
- the following compounds are particularly preferably used as phosphatidylinositols
- DMPI-Na dimystoylphosphatidylinositol
- DPPI-Na dipalmitoylphosphatidylinositol
- DSPI-Na disteraroylphosphatidylinositol
- the liposome components according to the invention are characterized in that they are added to any further liposome components in proportions of greater than 0 mol% up to 100 mol%.
- the liposomes produced by means of the liposome components according to the invention - in particular BIIC 1996-containing liposomes - have the following advantages.
- the content of the pharmaceutically active component can be greatly increased by adding the liposome components according to the invention. For this reason, in order to achieve a high active ingredient concentration, a cost-intensive increase in the concentration of the other liposome components can be dispensed with
- the liposome components according to the invention are indispensable for the simple production of active substance-containing liposomes in a size range ⁇ 200 nm
- the concentration of the solubilized drug can be controlled by varying the total lipid content
- lipid (s) are to be understood to mean all constituents of the liposome bilayer with the exception of the liposomally enclosed pharmaceutical substance
- the liposomes from the liposome components proposed according to the invention can be produced by various methods.
- the following examples explain the processes for the production of liposomes with lipophilic drugs for the lipid compositions according to the invention and are known per se from the prior art. [MJ Ostro, Liposomes, Marcel Dekker, New York, 1983; G. Gregroiadis, Liposome Technology Vol. I, Preparation of Liposomes, CRC Press Inc. Boca Raton, 1984]:
- the size of the liposomes resulting from spontaneous vesicle formation during hydration can be varied. This dispersion can take place through mechanical energy input of different origins, for example by simple hand shaking, use of shaking devices, by extrusion through membrane filters with a precisely defined pore size, extrusion under high pressure through various narrow nozzles, through the use of various stirring and mixing devices and through ultrasonication .
- liposomes containing active substances Due to the spontaneous vesicle formation of freeze-dried lipid-drug mixtures, liposomes containing active substances are formed during the hydration. During the hydration of freeze-dried liposomes, drug-containing liposomes are reconstituted
- Liposomes produced with the liposome components according to the invention can po, ⁇ v, sc, ⁇ c, dermal, intrapulmonal, nasal, ip, rectally, in ocular or be applied intracerebrally
- the lipids under consideration were weighed into a round-bottomed flask with a long neck and dissolved with a suitable mixture of chloroform and methanol, possibly using warmth. Drug dissolved in methanol was pipetted in. The solvent mixture was spun off on a rotary evaporator and dried. To completely remove residual solvent, the lipid film was subsequently dried in a vacuum drying cabinet. After gassing with nitrogen, the lipid film was stored at -18 ° C. until hydration. To prepare the liposomes, lipid film was hydrated with 5% (m / V) glucose solution. The hydration was carried out at 75 ° C.
- the liposome size was always less than 100 nm on average Filtration through a membrane filter with a pore size of 0.2 ⁇ m, the liposome size, the drug content and the lipid content were determined in the filtrate.
- DAB 10 filtration through bacteria-retaining filters
- the four lipids DSPG-Na, Pl-Na, DPPS and DPPA were tested in combination with 30 mol% HSPC for their inclusion capacity with regard to BIIC 1996 BS.
- a lipid concentration of 5 ⁇ mol / ml and a drug concentration of 10.2 mg were used / ml
- Fig. 2 shows the corresponding result, according to which only the lipids containing glycerol and inositol showed a satisfactory result.
- the quotient D / L denotes the molar ratio of liposomally enclosed BIIC 1996 BS and lipid Example 2
- HSPC / DSPG-Na was tested as a lipid mixture in varying compositions.
- the drug concentrations were varied between 0 mg / ml to 10.2 mg / ml
- FIG. 8 and FIG. 9 represent the results graphically, they demonstrate that with increasing amount of the drug used, the amount of the liposomally included drug increased linearly up to the saturation limit. The amount of BIIC 1996 BS included could thus be controlled excellently
- the drug concentrations were varied between 0 mg / ml to 10.2 mg / ml and the liposome size after production, Examined 2 days after manufacture and 28 days after manufacture.
- the storage conditions were 4 ° C and room temperature (19 - 24 ° C) with the exclusion of light.
- Liposome dispersions of the lipid composition HSPC / DSPG-Na. (30/70) with the drug concentration 3.5 mg / ml and HSPC / DSPG-Na / CH (21/49/30) with the drug concentration 3.0 mg / ml were used in one Lipid concentration of 45 ⁇ mol / ml nebulized with the Respirgard II ⁇ 10 nebulizing system.
- the nozzle gas flow was 6 l / min, the nebulization time 22.53 min + 2.13 min (x + SD). Before and after nebulization, the nebulizing solution in the reservoir was examined for the drug content.
- Fig. 14 illustrates the great content stability of the liposomes under consideration under very strong mechanical stress, such as occurs during nozzle atomization.
- phosphatidylglycerols and phosphatidylinositols in particular the structural formula of the sodium salt of phosphatidylglycerols and phosphatidylinositols [G Cevc, D Marsh, Phosphohpid Bilayers, Physical Pnnciples and Models, John Wiley & Sons Ine, New York, 1987, D Arnd , I Fichtner, Liposomes, Representation - Properties - Application, Akademie Verlag Berlin, 1986]
- FIG. 2 Influence of different lipids on the liposomal inclusion of BIIC 1996 BS (example 1)
- Lipid 5 ⁇ mol / ml The data shown are the arithmetic mean from 3 determinations. The error bars represent the standard deviation
- the data shown are the arithmetic mean values from 3 determinations.
- the error bars represent the standard deviation
- BIIC 1996 BS shows the influence of phosphatidyl-glycerol on the liposomal inclusion of BIIC 1996 BS in three-component lipid systems with constant cholesterol content (example 2) Inclusion rates 2 days after production.
- Lipid 45 ⁇ mol / ml The data shown are the arithmetic mean of 3 determinations. The error bars represent the standard deviation.
- Fig. 5 shows the influence of phosphatidyl-glycerol on the liposomal
- the data shown are the arithmetic mean values from 3 determinations.
- the error bars represent the standard deviation.
- Fig. 6 shows the influence of phosphatidyl-glycerol on the liposomal
- the data shown are the arithmetic mean values from 3 determinations.
- the error bars represent the standard deviation. shows the influence of the lipid concentration on the liposomal inclusion of BIIC 1996 BS (example 3)
- the data shown are the arithmetic mean values from FIG. 3
- the error bars represent the standard deviation
- the data shown are the arithmetic mean values from 3 determinations.
- the error bars represent the standard deviation
- the data shown are the arithmetic mean values from 3 determinations.
- the error bars represent the standard deviation 381 PC17EP97 / 03108
- Lipid composition HSPC / DSPG-Na / CH (30/70) use concentrations lipid 45 ⁇ mol / ml
- the data shown are the arithmetic mean values from 3 determinations.
- the error bars represent the standard deviation
- the data shown are the arithmetic mean values from FIG. 3
- Lipid composition HSPC / DSPG-Na (30/70) use concentrations lipid 45 ⁇ mol / ml
- the data shown are the arithmetic mean values from 3 determinations.
- the error bars represent the standard deviation.
- Fig. 13 shows the influence of storage conditions and use concentrations of the drug on the size of BIIC 1996 BS liposomes (Example 6).
- Liposome sizes after production (•), after 2 days (D), after 28 days after storage at 4 ° C ( ⁇ ) and after 28 days storage at room temperature (19 - 24 ° C) (O) with the light closed.
- Lipid composition HSPC / DSPG-Na (21/49/30)
- the data shown are the arithmetic mean values from FIG. 3
- Fig. 14 shows nebulization stability of BIIC 1996 BS liposome dispersions (Example 7).
- the liposome dispersions were nebulized using the Respirgard II ⁇ 10 system.
- the data shown are the arithmetic mean of 5 determinations.
- the error bars represent the standard deviation.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP09532939A JP2000513330A (ja) | 1996-06-15 | 1997-06-14 | リポソームとしての医薬製剤 |
EP97929185A EP0904058A1 (de) | 1996-06-15 | 1997-06-14 | Pharmazeutische zubereitung in form von liposomen |
CA002253285A CA2253285A1 (en) | 1996-06-15 | 1997-06-14 | Pharmaceutical preparation in the form of liposomes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19623950.8 | 1996-06-15 | ||
DE1996123950 DE19623950A1 (de) | 1996-06-15 | 1996-06-15 | Pharmazeutische Zubereitung in Form von Liposomen |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997048381A1 true WO1997048381A1 (de) | 1997-12-24 |
Family
ID=7797053
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/003108 WO1997048381A1 (de) | 1996-06-15 | 1997-06-14 | Pharmazeutische zubereitung in form von liposomen |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0904058A1 (ja) |
JP (1) | JP2000513330A (ja) |
CA (1) | CA2253285A1 (ja) |
DE (1) | DE19623950A1 (ja) |
WO (1) | WO1997048381A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002038575A1 (en) * | 2000-11-07 | 2002-05-16 | I.R.B. Istituto Di Ricerche Biotecnologiche S.R.L. | Glycerophosphoinositol derivatives as modulators of cytosolic a2 phospholipase |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005007240A1 (en) * | 2003-07-21 | 2005-01-27 | Vasogen Ireland Limited | Combination treatment of neurological disorders comprising phospholipids |
WO2008088581A2 (en) * | 2006-08-02 | 2008-07-24 | United Therapeutics Corporation | Liposome treatment of viral infections |
EP2410989A2 (en) | 2009-03-27 | 2012-02-01 | The Chancellor, Masters and Scholars of the University of Oxford | Cholesterol level lowering liposomes |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987007502A1 (en) * | 1986-06-06 | 1987-12-17 | Phares Pharmaceutical Research N.V. | Composition and method |
WO1990006775A1 (en) * | 1988-12-14 | 1990-06-28 | Liposome Technology, Inc. | A novel nonphospholipid liposome composition for sustained release of drugs |
EP0560138A1 (de) * | 1992-03-10 | 1993-09-15 | Bayer Ag | Liposomale Wirkstoff-Formulierungen und Verfahren zu ihrer Herstellung |
EP0622072A2 (en) * | 1993-04-02 | 1994-11-02 | Wakamoto Pharmaceutical Co., Ltd. | Stable aqueous dispersions containing liposomes |
WO1995030687A1 (de) * | 1994-05-07 | 1995-11-16 | Boehringer Ingelheim Kg | Neurokinin (tachykinin)-antagonisten |
-
1996
- 1996-06-15 DE DE1996123950 patent/DE19623950A1/de not_active Withdrawn
-
1997
- 1997-06-14 WO PCT/EP1997/003108 patent/WO1997048381A1/de not_active Application Discontinuation
- 1997-06-14 JP JP09532939A patent/JP2000513330A/ja active Pending
- 1997-06-14 CA CA002253285A patent/CA2253285A1/en not_active Abandoned
- 1997-06-14 EP EP97929185A patent/EP0904058A1/de not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987007502A1 (en) * | 1986-06-06 | 1987-12-17 | Phares Pharmaceutical Research N.V. | Composition and method |
WO1990006775A1 (en) * | 1988-12-14 | 1990-06-28 | Liposome Technology, Inc. | A novel nonphospholipid liposome composition for sustained release of drugs |
EP0560138A1 (de) * | 1992-03-10 | 1993-09-15 | Bayer Ag | Liposomale Wirkstoff-Formulierungen und Verfahren zu ihrer Herstellung |
EP0622072A2 (en) * | 1993-04-02 | 1994-11-02 | Wakamoto Pharmaceutical Co., Ltd. | Stable aqueous dispersions containing liposomes |
WO1995030687A1 (de) * | 1994-05-07 | 1995-11-16 | Boehringer Ingelheim Kg | Neurokinin (tachykinin)-antagonisten |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Derwent World Patents Index; * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002038575A1 (en) * | 2000-11-07 | 2002-05-16 | I.R.B. Istituto Di Ricerche Biotecnologiche S.R.L. | Glycerophosphoinositol derivatives as modulators of cytosolic a2 phospholipase |
CN1300155C (zh) * | 2000-11-07 | 2007-02-14 | I·R·B·生物技术研究院有限公司 | 作为胞液型磷脂酶的调制剂的甘油磷酸肌醇衍生物 |
US7625883B1 (en) | 2000-11-07 | 2009-12-01 | I.R.B. Istituto di Ricerche Biotechnologiche S.R.L. | Glycerophosphoinositol derivatives as modulators of cytosolic A2 phospholipase |
Also Published As
Publication number | Publication date |
---|---|
DE19623950A1 (de) | 1997-12-18 |
EP0904058A1 (de) | 1999-03-31 |
CA2253285A1 (en) | 1997-12-24 |
JP2000513330A (ja) | 2000-10-10 |
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