• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    A liposomal composition comprising a liposome and an aminoalkanesulfonic buffer is described and claimed.
    公开号:BE1022518B1
    申请号:E2015/5133
    申请日:2015-03-12
    公开日:2016-05-19
    发明作者:Nupur Dutta；Hardeep Oberoi；David Burkhart；Jay T. Evans
    申请人:Glaxosmithkline Biologicals S.A.；
    IPC主号:
    专利说明:

    IMMUNOGENIC LIPOSOMAL FORMULATION Statement Regarding Government-Funded Research
    Aspects of this invention have. .. with the support of the United States Government and under the terms of the NIH NO. HHSN272200900008C, the United States Government may have certain rights in the invention.
    Context
    Toll-4 receptor agonists (TLR4) are immunogenic compounds. TLR4 agonists have been formulated into liposomes for administration. Monophosphoryl lipid A is a known agonist of TLR4. 3-0-Deactivated monophosphoryl lipid A (MPL) is formulated in liposomal compositions in vaccines. In general, there is a need for improved liposomal compositions and particularly improved liposomal compositions of TLR4 agonists for administration to a human subject. Liposomal compositions of potent TLR4 agonists with high incorporation efficiency are desirable. Summary of the invention
    The present invention is directed to improved liposomes for use in pharmaceutical compositions.
    In one embodiment, the present invention provides a liposomal composition comprising lipids, suitably phospholipids, and aminoalkanesulfonic buffer such as HEPES, HEPPS / EPPS, MOPS, MOBS and PIPES.
    In another suitable embodiment, the present invention provides a liposomal composition comprising lipids such as phospholipids, and aminoalkyl glucosaminide phosphate (PGP), conveniently CRX-601.
    In another suitable embodiment, the present invention provides a liposomal composition comprising lipids, a,., - AG.P, and a buffer. aminoalkanesulfonic acid wherein the lipids are suitably phospholipids.
    In another embodiment, the present invention provides an improved method of producing a liposomal composition comprising the following: dissolution of a lipid, such as dioleoylphosphatidylcholine (usually "DOPC"), (optionally with cholesterol and / or a pharmaceutically active component, such as AGP), in an organic solvent, removing the solvent to produce a phospholipid film, adding the film to HEPES buffer. dispersion of the film, in the solution, and extrusion of the solution successively through polycarbonate filters to form unilamellar liposomes. The liposomal composition can be further filtered aseptically.
    These novel liposomal compositions remarkably exhibit high incorporation efficiency with AGPs, which are known to be potent and potentially reactogenic. Formulation of a liposomal AGP composition for pharmaceutical use as described herein may result in an improvement in the therapeutic index for the composition as compared to other formulations of the agonist. .
    In a suitable embodiment, a liposomal composition exhibits high incorporation of TLR4 agonists when the liposome is formed with cholesterol but also when the liposome is formed without cholesterol, providing benefits for the production and formulation of such liposomal compositions.
    The liposomes of the present invention are beneficial both in the production and use of a pharmaceutical composition. Other embodiments are disclosed in the descriptions. claims. provided .. here.
    Brief description of the drawings
    Figure 1 - LAL test data showing the incorporation efficiency determined by comparing the slope and the response time of the sample relative to the reference CRX-601 IN (0% incorporation).
    Figure 2 - LAL test data showing the incorporation efficiency determined by comparing the slope and the response time of the sample relative to the reference CRX-601 IN (0% incorporation).
    Figure 3 - LAL test data showing the incorporation efficiency determined by comparing the slope and the response time of the sample with reference CRX-527 Hepes (0% incorporation).
    Detailed Description of the Invention Liposomes
    The term "liposome (s)" generally refers to uni- or multilamellar lipid structures (particularly 2, 3, 4, 5, 6, 7, 8, 9, or 10 lamellar depending on the number of lipid membranes formed) containing an aqueous interior. Liposomes and liposomal formulations are well known in the state of the art. Lipids that are capable of forming liposomes include all substances with greasy or greasy properties. The lipids which may constitute the lipids in the liposomes may be chosen from the group comprising glycerides, glycerophospholipids, glycerophosphinolipids, glycerophospholipids, sulpholipids, sphingolipids, phospholipids, isoprenolides, steroids, d. sterols, archaeolipids, synthetic cationic lipids and carbohydrate-containing lipids.
    In a particular embodiment of the invention, the liposomes comprise a phospholipid. Suitable phospholipids include (but are not limited to): phosphocholine (PC) which is an intermediate in the synthesis of phosphatidylcholine; natural phospholipid derivatives: egg phosphocholine, soy phosphocholine, hydrogenated soy phosphocholine, sphingomyelin as natural phospholipids; and synthetic phospholipid derivatives: phosphocholine (didecanoyl-L-α-phosphatidylcholine [DDPC], dilauroylphosphatidylcholine [DLPC], dimyristoyl-phosphatidylcholine [DMPC], dipalmitoyl-phosphatidylcholine [DP.PC] .distearoyl-phosphatidylcholine [DSPC] ], dioleoylphosphatidylcholine [DOPC], 1-palmitoyl, 2-oleoylphosphatidylcholine [POPC], dielaidoylphosphatidylcholine [DEPC]), phosphoglycerol (1,2-dimyristoyl-sn-glycero-3-phosphoglycerol [DMPG], 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol [DPPG], 1,2-distearoyl-sn-glycero-3-phosphoglycerol [DSPG], 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol [ POPG]), phosphatidic acid (1,2-dimyristoyl-sn-glycero-3-phosphatidic acid [DMPA], dipalmitoylphosphatidic acid [DPPA], distearoylphosphatidic acid [DSPA]), phosphoethanolamine (1,2 -dimyristoyl-sn-glycero-3-phosphoethanolamine [DMPE], 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine [DPPE], 1,2-distearoyl-sn-glycero-3- phosphoethanolamine [DSPE], 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine [DOPE]), phosphoserine, polyethylene glycol [PEG] -phospholipid (mPEG-phospholipid, polyglycerin-phospholipid, functionalized phospholipid, terminal activated phospholipids) 1,2-Dioleoyl-3- (trimethylammonium) propane (DOTAP). In one embodiment, the liposomes
    include 1-palmitoyl-2-oleoyl-glycero-1,2-phosphoethanolamine. In one embodiment, the highly purified phosphatidylcholine is used and may be selected from the group consisting of phosphatidylcholine (egg,), hydrogenated phosphatidylcholine (egg), phosphatidylcholine (soybean) and hydrogenated phosphatidylcholine ( soy) . In another embodiment, the liposomes include phosphatidylethanolamine [POPE] or a derivative thereof or they can include sphingomyelin (SPNG).
    The size of the liposome can vary from 30 nm to 5 μm according to the phospholipid composition and the process used for their preparation. In particular embodiments of the invention, the size of the liposome will be in the range of 30 nm to 500 nm and in other embodiments 50 nm to 200 nm, suitably less than 200 nm. Dynamic scattering of laser light is a method used to measure the size of liposomes well known to those skilled in the art.
    In particular, the liposomes of the invention may comprise dioleoylphosphatidylcholine [DOPC] and a sterol, in particular cholesterol.
    Liposomal composition
    A "liposomal composition" is a prepared composition comprising a liposome and the content within the liposome, particularly including the lipids that form the bilayer (s) of the liposome, compounds other than lipids within the bilayer (s). (s) liposome, breast and associated compounds within or within the aqueous liposome, and compounds bound or associated with the outer layer of the liposome. Thus, in addition to the liposome lipids, a liposomal composition of the present invention may conveniently include, but is not limited to, pharmaceutically active components, vaccine antigens, adjuvants, excipients, carriers, and the like. and buffering agents. In a preferred embodiment, such compounds are complementary and / or are not significantly. .predictable "for. The stability or effectiveness of incorporation of AGP from the liposomal composition. "Liposomal Formulation" means a liposomal composition, such as those described herein, formulated appropriately with other compounds for storage and / or administration to a subject.
    Thus, a liposomal formulation of the present invention comprises a liposomal composition of the present invention, and may further include, but is not limited to, liposomal compositions outside the scope of the present invention, as well as pharmaceutically active compounds, vaccine antigens and adjuvants, excipients, carriers and buffering agents. In a preferred embodiment, such compounds are complementary and / or are not significantly detrimental to the stability or efficiency of incorporation of AGP from the liposomal composition of the present invention.
    Aminoalkyl glucosaminide phosphate compounds. AGPs are modulators of the Toll-4 receptor (TLR4). The Toll-4 receptor recognizes bacterial LPS (lipopolysaccharide) and when activated, initiates an innate immune response. PFAs are monosaccharide mimetics of bacterial LPS lipid A and have been developed with ether and ester linkages on the "acyl chains" of the compound. Methods of making such compounds are known and disclosed, for example, in WO 2006/016997, US Pat. Nos. 7,288,640 and 6,113,918, and WO 01/90129, which are incorporated herein by reference. in their entirety. Other AGP and related processes are disclosed in the patent # §20
    No. 7,129,219, US Pat. No. 6,525,028 and US Pat. No. 6,911,434. AGPs with ether linkages on the acyl chains employed in the composition of the invention are known and disclosed. in .WD .., 2.0.06 / 016997 which is incorporated herein by reference in its entirety. Of particular interest are the aminoalkyl glucosaminide phosphate compounds shown and described according to formula (III) in paragraphs [0019] to [0021] in WO 2006/016997.
    The aminoalkyl glucosaminide phosphate compounds employed in the present invention have the structure represented by the following Formula 1:
    (Formula 1) wherein m is 0 to 6 n is 0 to 4; X is O or S, preferably O; Y represents O or NH; Z represents O or H; each R 1, R 2, R 3 is independently selected from the group consisting of C 1 -C 20 acyl and C 1 -C 20 alkyl; R4 is H or Me; R 5 is independently selected from the group consisting of -H, -OH, -C 1-4 alkoxy, -PO 3 R 8 R 9, -OPO 3 R 8 R 9, -SO 3 R 8, -OSO 3 R 8, -NR 8 R 9, -SR 5, -CN, -NO 2, -CHO, -CO2R8, and -CONR8R9, wherein R8 and R9 are each independently selected from H and C1-C4alkyl-and each R6 and R7 is independently H or Ρ03Η2.
    In formula 1, the configuration of the 3 stereogenic centers to which normal fatty acyl residues (i.e., acyloxy or secondary alkoxy residues, eg, RiO, R20, and R30) are attached, is R or S, preferably R (as it is designated by the Cahn-Ingold-Prelog priority rules). The configuration of the stereogenic centers of the aglycone to which R4 and R5 are attached may be R or S. All stereoisomers, both enantiomers and diastereoisomers, and. their mixtures are considered to fall within the scope of the present invention.
    The number of carbon atoms between the X heteroatom and the nitrogen atom of the aglycone is determined by the variable "n", which may be an integer from 0 to 4, preferably an integer of 0 to 2.
    The length of the normal fatty acid chain R 1, R 2 and R 3 may be from about 6 to about 16 carbons, preferably from about 9 to about 14 carbons. The lengths of the chains may be the same or different. Some preferred embodiments include chain lengths where R 1, R 2 and R 3 are 6 or 10 or 12 or 14.
    Formula 1 encompasses L / D-seryl-, -threonyl-, -cysteinyl ether and lipid ester AGP, both agonists and antagonists and their homologs (η = 1 to 4), as well as various bio-isosteres. of carboxylic acid (i.e., R5 is an acid group capable of forming a salt, the phosphate may be in the 4 or 6 position of the glucosamine unit, but preferably it is in the 4 position) .
    In a preferred embodiment of the invention employing an AGP compound of Formula 1, n is 0, R5 is CO2H, R6 is P03H2, and R7 is H. This preferred AGP compound is represented by the following structure of formula
    (Formula la) wherein X is O or S; Y represents O or NH; Z represents O or H; each R 1, R 2, R 3 is independently selected from the group consisting of C 1 -C 20 acyl and C 1 -C 20 alkyl; and R4 is H or methyl.
    In formula la, the configuration of the 3 stereogenic centers to which normal fatty acyl residues (i.e., secondary acyloxy or alkoxy residues, eg, RiO, R20, and R30) are attached, is R or S, preferably R (as it is designated by the Cahn-Ingold-Prelog priority rules). The configuration of the stereogenic centers of the aglycone to which R4 and CO2H are attached may be R or S. All stereoisomers, both enantiomers and diastereomers, and mixtures thereof, are considered to be within the scope of this invention. invention.
    Formula la encompasses L / D-seryl-, -threonyl-B12C-cysteinyl ether and lipid ester AGP, both agonists and antagonists.
    In both formula I and formula Ia, Z is set at 0 by a double bond. or two hydrogen atoms which are each attached by a single bond. That is, the compound is bound by an ester when Z = Y = 0; bound by an amide when Z = 0 and Y = NH; and bound by an ether when Z = H / H and Y = 0.
    Especially preferred compounds of formula 1 are called CRX-601 and CRX-527. Their structures are represented as follows:
    BE2C
    In addition, another preferred embodiment employs CRX-547 having the structure shown. f
    Still other embodiments include AGPs such as CRX 602 or CRX 526 providing increased stability to AGPs with short secondary acyl or alkyl chains.
    Other AGPs suitable for use in the present invention include CRX 524 and CRX 529.
    tampons
    In one embodiment of the present invention, a liposomal composition is buffered using a zwitterionic buffer. Suitably, the zwitterionic buffer is an aminoalkanesulfonic acid or a suitable salt. Examples of aminoalkanesulfonic buffers include, but are not limited to, HEPES, HEPPS / EPPS, MOPS, MOBS and PIPES. Preferably, the buffer is a pharmaceutically acceptable buffer, suitable for use in humans, as for use in a commercial injection product. Most preferred is the HEPES buffer. Liposomal storage can appropriately take an AGP.
    In appropriate embodiments of the present invention, the liposomes are buffered using HEPES having a pH of about 7.
    In a preferred embodiment of the present invention, the AGP CRX-601, CRX-527 and CRX-547 are included in a buffered liposomal composition using HEPES having a pH of about 7. The buffers can be used with a appropriate amount of saline or other excipient to obtain the desired isotonicity. In a preferred embodiment, 0.9% saline is used.
    HEPES: CAS Registry Number: 7365-45-9 CsHigNaCgS
    1-piperazine-ethanesulfonic acid, 4- (2-hydroxyethyl) -HEPES is a zwitterionic buffer designed to buffer the physiological pH range from about 6 to about 8 (e.g., 6.15 to 8.35) and more specifically to a more useful range from about 6.8 to about 8.2 and, as in the present invention, from about 7 to about 8 or from 7 to 8, and preferably from about 7 to less than 8. HEPES ee2C generally a white crystalline powder and has the molecular formula: C8H18N2O4S of following structure:
    HEPES is well known and commercially available. (See, for example, Good et al., Biochemistry 1966).
    Liposomal preparation
    Conventional methods for making liposomes include, but are not limited to, methods reported in Liposomes: A Practical Approach, Torchilin VP, Volkmax Weissig Oxford University Press, 2003 and are well known in the state of the art. .
    In an appropriate method of making a liposomal composition of the present invention, an AGP (e.g., CRX-601 (20 mg)) and DOPC (specifically, 1,2-dioleoyl-sn-glycero-3-phosphocholine ) (400 mg)) and optionally a sterol (for example, cholesterol (100 mg)) are dissolved in an organic phase of chloroform or tetrahydrofuran in a round bottom flask. The organic solvent is removed by evaporation on a rotary evaporator and further with a high pressure under vacuum for 12 hours. To the mixed phospholipidic film thus obtained are added 10 ml of an aminoalkanesulfonic buffer such as 10 mM HEPES or a 10 mM HEPES-physiological saline buffer pH 7.2. The mixture is sonicated on a water bath (20 to 30 ° C) and vortexed intermittently until the film along the walls of the flask is dispersed in the solution (30 min to 1.5 h) . The solution is then extruded successively through polycarbonate filters using a lipid mini-extruder (Lipex ™ Extruder (Northern Lipids Inc., Canada)) to form unilamellar liposomes. The liposomal composition is then aseptically sterilized using a 0.22 μm filter in a sterile depyrogenic container. The average particle size of the resulting formulation measured by dynamic light scattering is 80 to 120 nm with a net negative zeta potential. The formulation represents final target concentrations of 2 mg / ml CRX-601, 10 mg / ml cholesterol, and 40 mg / ml total phospholipid. The aminoalkyl glucosaminide 4-phosphate (AGP) CRX-601 used in these studies can be synthesized as previously described (Bazin, 2008 32447 / id), and purified by chromatography (up to> .95% purity). CRX-601, either in the starting material or in the final product, can be quantified by a conventional reverse phase HPLC analytical method. CRX-601 formulated in HEPES buffer (pH = 7.0) achieved fivefold the desired reduction in particle size compared to the liposome hydration buffer ("LHB", phosphate-based, pH = 6.1). Rehydration of CRX-601 lipid films in HEPES buffer required four times less total pressure and time to formulate liposomes compared to LHB phosphate buffer. This is a significant improvement since it releases both energy and time and exerts far less stress on AGP during liposome treatment.
    In one embodiment, the appropriate ranges of the components of a liposomal composition comprise a lipid in a range of about 3 to 4% w / v, a 1% w / v sterol, an active component, such as an AGP, in the range of 0.1 to 1% w / v and a 10mM aminoalkanesulfonic buffer. In one embodiment, the sterol is suitably present in a range of 0.5 to 4% w / v. In addition, in one embodiment, the lipid / sterol / active component ratio is about 3 to 4/1 / 0.1 to 1.
    Examples
    Example 1 - Lipid Compatibility Study of the CRX-601 Formulation
    Eight lipids were screened in a study with CRX-601 to find the optimal liposomal formulation for CRX-601 leading to maximum stability of the active pharmaceutical component (CRX-601) and to acceptable pyrogenicity and / or toxicity that can be associated with the adjuvant.
    Lipex Extruder ™ was used to prepare the formulations. 10mM HEPES at pH = 7.0, was chosen as the hydration buffer. Liposomal formulations were prepared at a target concentration of 2 mg / ml in HEPES buffer at pH = 7.0. These lipid formulations were placed in real time stability at a temperature between 2 and 8 ° C for 6 months and accelerated stability at 40 ° C for 14 days to monitor the degradation of CRX-601 by RP-HPLC over time , as well as any change in appearance, particle size, and zeta potential to represent aggregation, and the liming amoebocyte lysate (LAL) chromogenic assay to represent changes in CRX-601 incorporation percentage .
    Table 1 shows the t = 0 (treatment data) for all prepared liposomes.
    Table 1
    c Incorporation efficiency was determined by comparing the slope and response time of the sample against the reference CRX-601 IN (0% incorporation) from the LAL test data. LAL test data at t = 0 shown below showed good incorporation for CRX-601 in DOPC., DOPCrCho.1, DOPC DC.-Chol, DOTAP, and DOTAP-Chol, and for CRX-527 in DOPC, Figures 1 and 3. The rest of the formulations showed poor incorporation as can be seen in Figure 2.
    Example 2 - Analysis of Incorporation Efficiency
    To determine the effect of cholesterol on the incorporation of CRX-601 into liposomes, LAL tests were performed on various liposomal compositions with and without cholesterol. The data obtained (not shown) confirms previous work with LAL tests showing that the DOPC and DOPC-cholesterol compositions exhibit surprisingly high levels of incorporation of CRX-601. However, the results of these LAL tests have not been sensitive or consistent enough to draw any conclusions regarding the effect of cholesterol on incorporation.
    Pyrogenicity tests on rabbits were used as a proxy for CRX-601 incorporation into liposomes and as a measure of their stability in biological media. The tests were performed at Pacific Biolabs (Hercules, CA) according to their SOP of 16E-02. The individual temperature increases of three rabbits per test are shown in the table below.
    The data in Table 2 indicate that liposomal formulations ... with. DCPC. with up to 4, mg ... of. ,, CRX-601 / ml prepared with or without cholesterol are non-pyrogenic up to a dose of 1000 ng / kg. This lack of pyrogenicity corresponds to a 400-fold improvement in free CRX-601 (maximum non-pyrogenic dose of 2.5 ng / kg), and indicates a> 99% incorporation of CRX-601 into the liposome bilayer.
    Table 2
    Representative measures of the pyrogenicity test in rabbits for liposomal formulations with DOPC prepared with or without cholesterol. The values in parentheses represent, the maximum change of. temperature for three animals during the analysis period. An increase in temperature of 0.5 ° C or more is considered a pyrogenic response. The symbols P and F indicate, respectively, a response "success" or "failure". .
    The data from Table 3 indicate that liposomal formulations with DOPC-cholesterol with up to 8 mg of CRX-601 / ml are non-pyrogenic up to a dose of 500 ng / kg. This lack of pyrogenicity corresponds to an improvement. *, 2.00 .times. .superior .. au. CRX-601 free. (Maximum non-pyrogenic dose of 2.5 ng / kg), and indicates> 99% incorporation of CRX-601 into the liposome bilayer.
    Table 3
    Representative measures of the pyrogenicity test in rabbits for liposomal formulations with DOPC prepared with cholesterol. Values in parentheses represent the maximum change in temperature for three animals during the analysis period. An increase in temperature of Q. 5 ° C or higher is. considered a pyrogenic response. The symbols P and F respectively indicate a "success" or "failure" response. *
    CRX-527 is the ester analogue of CRX-601. The data from Table 4 indicate that liposomal formulations with DOPC-cholesterol with up to 2 mg CRX-527 / ml are non-pyrogenic up to a dose of 500 ng / kg. This lack of pyrogenicity suggests a very high incorporation (potentially> 99%) of CRX-601 into the liposome bilayer. Interestingly, unlike CRX-601, CRX-527 in the liposomal formulation with DOPC (i.e., in the absence of cholesterol), has been shown to be pyrogenic at 500 ng / kg.
    Table 4
    Good incorporation results are also presented in Table 5 for cationic liposomes with DOTAP and DOTAP-cholesterol with CRX-601. I *
    Table 5
    权利要求:
    Claims (25)
    [1]
    A liposomal composition comprising a liposome and an aminoalkanesulfonic buffer.
    [2]
    2. Liposomal composition according to the preceding claim, wherein the aminoalkanesulfonic buffer is selected from the group comprising HEPES, HEPPS / EPPS, MOPS, MOBS and PIPES.
    [3]
    A liposomal composition according to any one of the preceding claims, wherein the aminoalkanesulfonic buffer is HEPES. A liposomal composition according to any one of the preceding claims, wherein the lipid which constitutes the liposomes is selected from the group consisting of glycerides, glycerophospholipids, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, phospholipids, isoprenolides, steroids, stearins, sterols, archaolipids, synthetic cationic lipids and carbohydrate lipids.
    [5]
    A liposomal composition according to any one of the preceding claims wherein the lipids in liposomes are phospholipids.
    [6]
    A liposomal composition according to any one of the preceding claims, wherein the lipids in the liposome are dioleoyl phosphatidylcholine (DOPC).
    [7]
    A liposomal composition according to any one of the preceding claims, wherein the lipids in the liposome are 1,2-dioleoyl-3- (trimethylammonium) propa2 (DOTAP).
    [8]
    A liposomal composition according to any one of the preceding claims, further comprising a sterol and in particular cholesterol.
    [9]
    A liposomal composition comprising an AGP incorporated in the liposome, wherein said liposome comprises dioleoyl phosphatidylcholine [DOPC] in the absence of a sterol.
    [10]
    10. The liposomal composition according to the preceding claims, wherein the AGP is CRX-601.
    [11]
    11. The liposomal composition according to the preceding claims, wherein the AGP is present in an amount greater than 10 mg / ml. '
    [12]
    Liposomal composition according to the preceding claims, wherein the AGP is present in an amount of less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3. , less than 2 or less than 1 mg, but greater than 0 mg / ml.
    [13]
    13. A liposomal composition according to the preceding claims, wherein the AGP is present in an amount greater than 0 mg / ml, but less than or equal to 10 mg / ml.
    [14]
    Liposomal composition according to the preceding claims, wherein the AGP is present in an amount between 30 Dg / ml and 6 mg / ml.
    [15]
    Liposomal composition according to any one of the preceding claims, wherein the liposome is multilamellar. ,,, 16. .Liposomal ... composition according to any one of the preceding claims, wherein the liposome is 2, 3, 4, 5, 6, 7, 8, 9, or 10 lamellar.
    [17]
    Liposomal composition according to any one of the preceding claims, wherein the liposome is unilamellar.
    [18]
    18. A liposomal composition according to any one of the preceding claims, wherein the size of the liposome will be in the range, from 50 nm to 500 nm and in other embodiments from 50 nm to 200 nm. * »
    [19]
    19. A liposomal composition according to any one of the preceding claims, wherein the size of the liposome will be in the range of about 80 to 120 nm.
    [20]
    The liposomal composition of any one of the preceding claims, wherein the liposomal structures contain an aqueous interior.
    [21]
    21. Liposomal composition according to any one of the preceding claims, further comprising a lipid A mimetic, a TLR4 ligand, or an AGP.
    [22]
    Liposomal composition according to any one of the preceding claims, wherein the active compound is an aminoalkyl glucosaminide phosphate having the structure represented by the formula I:

    (Formula 1) wherein m is 0 to 6 n is 0 to 4; X is 0 or S, preferably 0; Y represents O or NH; Z represents O or H; Each R 1, R 2, R 3 is independently selected from the group consisting of C 1 -C 20 acyl and C 1 -C 20 alkyl; R4 is H or Me; R5 is independently selected from the group consisting of -H, -OH, -C1-C4 alkoxy, -PO3R8R9, -OPO3R8R9, -SO3R8, -SO3Rs, -NR8R9, -SRs, -CN, -NO2, -CHO, -CO2R8, and -CONR8R9, wherein R8 and R9 are each independently selected from H and C1-C4alkyl; and each R6 and R7 is independently H or PO3H2.
    [23]
    23. Liposomal composition according to any one of the preceding claims, further comprising an active compound (lipid A mimetic)
    [24]
    A liposomal composition according to any of the preceding claims, wherein the AGP is selected from the group of CRX 527, 601, 602, 547, 524 and 529.
    [25]
    25. A method of improving the production of a liposomal composition comprising: Preparation of a phospholipidic film and b. Addition of the phospholipid film to an amino-alkanesulfonic buffer
    [26]
    26. A process for producing a liposomal composition comprising the steps of: a. dissolving a lipid, such as DOPC (optionally with cholesterol and / or a pharmaceutically active component, such as an AGP) in an organic solvent, b. removing the solvent to produce a phospholipidic film, * c. adding the phospholipid film to an amino-alkanesulfonic buffer, d. the dispersion of the film in the solution, and e. extruding the solution successively through polycarbonate filters to form unilamellar liposomes.
    [27]
    27. The method according to the preceding claim, further comprising the step of aseptically filtering the extruded liposomes.
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    同族专利:
    公开号 | 公开日
    WO2015136480A1|2015-09-17|
    US20170071967A1|2017-03-16|
    JP2017511802A|2017-04-27|
    CA2942235A1|2015-09-17|
    AU2015228387A1|2016-10-27|
    KR20160127828A|2016-11-04|
    CN106456545A|2017-02-22|
    EP3116480A1|2017-01-18|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
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    法律状态:
    2021-12-16| MM| Lapsed because of non-payment of the annual fee|Effective date: 20210331 |
    优先权:
    申请号 | 申请日 | 专利标题
    US201461952118P| true| 2014-03-12|2014-03-12|
    US61/952,118|2014-03-12|
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