US2008089932A1PendingUtilityA1
Amphoteric liposomes, a method of formulating an amphoteric liposome and a method of loading an amphoteric liposome
Est. expiryOct 13, 2026(~0.2 yrs left)· nominal 20-yr term from priority
A61K 9/1272A61K 31/713Y02P20/582A61K 9/127
66
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Claims
Abstract
An amphoteric liposome composed of a mixture of lipids, said mixture comprising a cationic amphiphile, an anionic amphiphile and optionally one or more neutral amphiphiles, at least one of said cationic and anionic amphiphiles being chargeable and the respective amounts of said cationic and anionic amphiphiles being selected such there is a stoichiometric excess of positively charged cationic amphiphile at a first lower pH, a stoichiometric excess of negatively charged anionic amphiphile at a second higher pH and said mixture has an isoelectric point intermediate said first and second pHs; characterised in that said positively charged cationic and negatively charged anionic amphiphiles are adapted to form a lipid salt with one another at said isoelectric point. Also disclosed are methods of predicting the fusogenicity of an amphoteric liposome at a given pH, formulating an amphoteric liposome and loading an amphoteric liposome with a cargo moiety.
Claims
exact text as granted — not AI-modified1 . An amphoteric liposome comprising a mixture of lipids, said mixture including one or more anionic amphiphiles and one or more cationic amphiphiles which form one or more lipid pairs and having an isoelectric point, wherein said one or more of said lipid pairs are capable of forming a lipid salt at said isoelectric point of said mixture, with the provision that said lipid pairs do not include DODAC/CHEMS; DDAB/CHEMS; DOTAP/DOGS; DOTAP/DMGS; DOTAP/DPGS; DOTAP/CHEMS;CHIM/CHEMS; CHIM/DMGS; CHIM/DOGS; H is Chol/CHEMS; H is Chol/DMGS; H is Chol/DPGS; H is Chol/DOGS; H is Chol/DPPS; MoChol/CHEMS; MoChol/DMGS; MoChol/DPGS; MoChol/DOGS; MoChol/Cetyl-P; MoChol/DMPS; MoChol/DPPS; DC-CHOL/DOPA; DOTAP+CHIM/CHEMS; DC-Chol/Chems; DOIM/DMGS; DOIM/DOGS; and DOTAP/oleic acid.
2 . The amphoteric liposome as claimed in claim 1 , further comprising one or more neutral amphiphiles.
3 . The amphoteric liposome as claimed in claim 2 , said liposome having an isoelectric point in the range pH 4 to pH 8.
4 . The amphoteric liposome as claimed in claim 2 , wherein said liposome adopts a stable lamellar phase at pH 7 to 8.
5 . The amphoteric liposome as claimed in claim 2 , wherein said lipid salt has a κ salt value of less than about 0.35.
6 . The amphoteric liposome as claimed in claim 2 further comprising counter-cations and counter-anions, wherein said counter-cations have a molecular volume of at least 50 A 3 and are selected from to sodium, tris(hydroxyl-methyl)aminomethane, tris-hydroxyethylaminomethane, triethylamine, arginine and L-arginine.
7 . The amphoteric liposome as claimed in claim 2 , wherein said liposome is of amphoter I type, said liposome comprising a lipid salt with a κ salt smaller than 0.34 and a difference between KSalt and κ total (pH 8) for C/A=0.5 of the lipid salt of greater than 0.08.
8 . The amphoteric liposome as claimed in claim 7 , wherein the anionic amphiphile comprises a tail group having a molecular volume smaller than 420 Å 3 , said tail group being selected from sterols and dimyristoylethylenglycols.
9 . The amphoteric liposome as claimed in claim 7 , wherein the anionic amphiphile comprises a head group having a molecular volume between 70 A 3 and 190 Å 3 , said head group being selected from hemimalonates, hemisuccinates, hemiglutarates, hemiadipates, cyclohexanoic diacids, glucuronic acids and homologues thereof.
10 . The amphoteric liposome as claimed in claim 7 , wherein the cationic amphiphile comprises a head group having a molecular volume between 40 and 100 Å 3 , said head group being selected from methylamine, dimethylamine, trimethylamines, tetramethylammonium salts, N-methylpyridinium salts, trimethyl-hydroxyethylammonium salts, N-a trimethylammoniumacetyl salts, dimethylaminoethylcarbamates, N-Methyl-mono(hydroxymethyl)aminomethane, N-Methyl-bis(hydroxymethyl)aminomethane and homologues thereof.
11 . An amphoteric liposome of amphoter I type, said liposome comprising a mixture of lipids, said mixture including one or more anionic amphiphiles and one or more cationic amphiphiles which form one or more lipid pairs and having an isoelectric point, said one or more cationic amphiphiles having a head group, said one or more of said lipid pairs being capable of forming a lipid salt at said isoelectric point of said mixture, said lipid salt having k(salt)<0.35, wherein said head group of the cationic amphiphile comprises a tertiary or secondary amine.
12 . The amphoteric liposome as claimed in claim 2 , wherein said liposome is of amphoter II type, wherein said lipid salt has a k(salt) of <0.34.
13 . The amphoteric liposome as claimed in claim 12 , wherein the cationic amphiphile comprises an apolar tail group which is a sterol.
14 . The amphoteric liposome as claimed in claim 12 , wherein the cationic amphiphile comprises an apolar tail group and the ratio of said cationic amphiphile to said anionic amphiphile in said lipid mixture (C/A) is greater than 1; wherein further said tail group has a molecular volume smaller than 420 A 3 , said tail group being selected from the group consisting of sterols and dimyristoylethylenglycols, and wherein the lipid anion tail groups have a molecular volume larger than 400 A 3 , said groups being selected from but not limited to diacylethylenglycols, most preferred dipalmitoyl-distearoyl-palmitoyloleoyl- or dioleoylethylenglycols.
15 . The amphoteric liposome as claimed in claim 14 , wherein the cationic amphiphile comprises a cationic polar head group and said anionic amphiphile comprises an anionic polar head group, and ratio of said cationic amphiphile to said anionic amphiphile in said lipid mixture (C/A) is about 1 or greater than 1; wherein the cationic head group has a molecular volume between 70 A 3 and 160 A 3 , said head group being selected from the group consisting of morpholines, propylimidazols, 3-imidazol-1-yl-propyl carbamates, piperazine 4-N-aminoethyl carbamoyls, 2-(4-Imidazolyl)ethylamine hemisuccinates, 1-[2-carboxyethyl]2-methyl-3-(2-hydroxyethyl)imidazolinium salts, ethylphosphocholines, N-Morpholino ethylamine hemisuccinates, 1-Methyl-4-choline-succinic acid diesters and homologues of said compounds; and wherein the anionic head group has a molecular volume between 40 and 100 A 3 .
16 . The amphoteric liposome as claimed in claim 12 , wherein the C/A ratio is about 1 and said anionic amphiphile comprises an anion lipid tail group having a molecular volume smaller than 420 A 3 , said anion lipid tail group being selected from the group consisting of sterols and dimyristoylethylenglycols.
17 . The amphoteric liposome as claimed in claim 12 , wherein the cationic amphiphile comprises a cationic polar head group and said anionic amphiphile comprises an anionic polar head group, and ratio of said cationic amphiphile to said anionic amphiphile in said lipid mixture (C/A) is lower than 1, wherein the cationic head group has a molecular volume of less than 130 A 3 , said cationic head group being selected from the group consisting of imidazols, methylimidazols, ethylimidazols, morpholins, methylmorpholins, ethylmorphlins, N-Methyl-tris(hydroxymethyl)aminomethanes, 3-imidazol-1-yl-propyl carbamates, piperazine 4-N-aminoethyl carbamoyls, N-Methyl-mono(hydroxymethyl)aminomethanes, N-Methyl-bis(hydroxymethyl)aminomethanes and homologues thereof, and said anionic head group has a molecular volume of less than 130 A 3 said anionic head group being selected from the group consisting of hemimalonates, hemisuccinates, hemiglutarates, hemiadipates, cyclohexanoic diacids and homologues thereof.
18 . The amphoteric liposome as claimed in claim 2 , said liposome comprising a cationic amphiphile selected from the group consisting of DmC4Mo2, DmC3Mo2, C3Mo2, C5Mo2, C6Mo2, C8Mo2 and C4Mo4.
19 . The amphoteric liposome as claimed in claim 6 , wherein said mixture comprises up to about 65 mol. % of one or more neutral amphiphiles.
20 . The amphoteric liposome as claimed in claim 19 , wherein k(min) is smaller than 0.34; and the difference between k(min) and k(total pH8)>0.08.
21 . The amphoteric liposome as claimed in claim 2 , wherein cholesterol is essentially the only neutral lipid and comprises more than 80 mol % of the total neutral lipids of said liposome.
22 . The amphoteric liposome as claimed in claim 2 , wherein cholesterol is the only neutral lipid.
23 . A method of formulating amphoteric liposomes comprising:
(i) selecting an anionic amphiphile, a cationic amphiphile, each of said anionic and cationic amphiphiles having respective polar head and apolar tail groups, and optionally one or more neutral amphiphiles, at least one of said anionic and cationic amphiphiles being chargeable; (ii) calculating the κ values for each of said anionic and cationic amphiphiles, when uncharged and when charged and associated respectively with predetermined cationic and anionic counterions, and said one or more optional neutral amphiphiles and the κ salt value for a lipid salt comprising said anionic and cationic amphiphiles in charged form, K being the ratio of the molecular volume of the polar head group V head to the molecular volume of the apolar tail group V apolar of the respective species, the molecular volumes of the polar head groups of the charged anionic and cationic amphiphiles including the respective counterions, and κ salt being defined as: κ salt = V head ( cat ) + V head ( an ) V apolar ( cat ) + V apolar ( an ) wherein V head (cat) is the molecular volume of the polar head group of the cationic amphiphile without the respective counter-anion, V head (an) is the molecular volume of the polar head group of the anionic amphiphile without the respective counter-cation, V apolar (cat) is the molecular volume of the apolar tail group of the cationic amphiphile and V apolar (an) is the molecular volume of the apolar tail group of the anionic amphiphile; (iii) modelling the function κ total (pH) for a lipid mixture of said anionic and cationic amphiphiles and said one or more optional neutral amphiphiles, assuming said cationic and anionic amphiphiles form said lipid salt when charged, the respective amounts of said amphiphiles in said lipid mixture being chosen such that said mixture of lipids has an isoelectric point between a first lower pH and a second higher pH and has a stoichiometric excess of positively charged cationic amphiphile at said first pH and a stoichiometric excess of negatively charged anionic amphiphile at said second pH, κ total (pH) being defined as: κ total ( pH ) = κ an · c an ( pH ) + κ cat · c cat ( pH ) + κ an - · c an - ( pH ) + κ cat + · c cat + ( pH ) + κ salt · c salt ( pH ) + ∑ κ n · c n wherein c an (pH), c cat (pH), can (pH), c cat+ (pH) and c salt (pH) are the respective concentrations in the lipid mixture of the uncharged anionic, uncharged cationic, charged anionic and charged cationic amphiphiles and said lipid salt as a function of pH, c n is the concentration in the lipid mixture of the or each optional neutral amphiphile, and κ an , κ cat , κ an -, κ cat + , κ salt and κ n are the respective K values for the uncharged anionic, uncharged cationic, charged anionic and charged cationic amphiphiles, said lipid salt and the or each optional neutral amphiphile; (iv) determining that κ total (pH) exhibits a minimum at said isoelectric point; (v) making liposomes composed of said lipid mixture and empirically confirming that said mixture exhibits a stable lamellar phases at said second pH's and optional at said first pH's and a fusogenic, hexagonal phase around said isoelectric point; and thereafter (vi) manufacturing an amphoteric liposome composed of said lipid mixture.
24 . The method as claimed in claim 23 , wherein said molecular volumes are calculated by molecular modelling.
25 . The method as claimed in claim 23 , wherein said anionic and cationic amphiphiles and their respective amounts are selected such that said lipid mixture exhibits an isoelectric point in the range pH 4 to pH 8.
26 . The method as claimed in claim 23 , wherein said counter-cations have a molecular volume of at least 50 A 3 .
27 . The method as claimed in claim 26 , wherein said counter-cations are selected from sodium,
tris(hydroxymethyl)aminomethane, tris-hydroxyethylaminomethane and triethylamine.
28 . The method as claimed in claim 27 , wherein said counter-cations are sodium.
29 . An amphoteric liposome formulated according the method as claimed in claim 23 , wherein said lipid salt comprises a chargeable anionic amphiphile and a chargeable cationic amphiphile and has a κ salt <0.34.
30 . The amphoteric liposome as claimed in claim 29 , wherein said anionic amphiphile is selected from the group consisting of Chems, DMGS, DMGM, DMGG, DMGA, DMAS, DMAM, DMAG, DMAA, DOGS, DOGM, DOGG, DOGA, DOAS, DOAM, DOAG, DOAA, DMS, DMM, DMG, DMA, DOS, DOM, DOG, DOA, Chol-C3, Chol-C5 and Chol-C6.
31 . The amphoteric liposome as claimed in claim 30 , wherein said cationic amphiphile is cholesterol-based or based on diacylglycerols.
32 . The amphoteric liposome as claimed in claim 31 , wherein said cholesterol-based cationic amphiphile is selected from the group consisting of MoChol, Chim, H is Chol and Desh4.
33 . An amphoteric liposome formulating according the method as claimed in claim 23 , wherein said lipid salt comprises a chargeable anionic amphiphile and a chargeable cationic amphiphile and has a κ salt <0.45 and wherein said chargeable cationic amphiphile is selected from the group consisting of DmC4Mo2, DmC3Mo2, C4Mo4, C3Mo3, C3Mo2, C5Mo2, C6Mo2 and C8Mo2 and wherein said chargeable anionic amphiphile is selected from the group comprising Chems, DMGS, DMGM, DMGG, DMGA, DMAS, DMAM, DMAG, DMAA, DOGS, DOGM, DOGG, DOGA, DOAS, DOAM, DOAG, DOAA, DMS, DMM, DMG, DMA, DOS, DOM, DOG, DOA, Chol-C3, Chol-C5 and Chol-C6.
34 . An amphoteric liposome formulated according the method as claimed in claim 23 , wherein said lipid salt is comprises an excess of a chargeable anionic amphiphile and a cationic amphiphile, having a κ salt <0.34 and a difference between and κ total (pH 8) for C/A=0.5 and κ salt >0.08.
35 . The amphoteric liposome as claimed in claim 34 , wherein said chargeable anionic amphiphile is selected from the group consisting of Chems, DMGS, DMGM, DMGG, DMGA, DMAS, DMAM, DMAG, DMAA, DOGS, DOGM, DOGG, DOGA, DOAS, DOAM, DOAG, DOAA, DMS, DMM, DMG, DMA, DOS, DOM, DOG, DOA, Chol-C3, Chol-C5 or Chol-C6 and fatty acids.
36 . An amphoteric liposome formulated according the method as claimed in claim 23 , wherein said lipid salt is comprises an excess of a chargeable anionic amphiphile and a cationic amphiphiles and has a κ salt <0.34; and wherein saidcationic amphiphile is selected from the group consisting of DDAB, DC-Chol, DAC-Chol, TC-Chol, DOTAP DOEPC and CTAB and said chargeable anionic lipid is selected from the group comprising DMGS, DMGM, DMGG, DMGA, DMAS, DMAM, DMAG, DMAA, DOGS, DOGM, DOGG, DOGA, DOAS, DOAM, DOAG, DOAA, DMS, DMM, DMG, DMA, DOS, DOM, DOG, DOA, Chol-C3, Chol-C5 and Chol-C6.
37 . An amphoteric liposome formulated according the method as claimed in claim 23 , wherein said lipid salt comprises an excess of a chargeable cationic amphiphile and an anionic amphiphile and said cationic lipid is selected from the group consisting of MoChol, Chim, H is Chol or Desh4, DmC4Mo2, DmC3Mo2, C4Mo4, C3Mo3, C3Mo2, C5Mo2, C6Mo2 and C8Mo2, DOIM and DPIM.
38 . An amphoteric liposome formulated according the method as claimed in claim 23 , wherein said optional neutral amphiphile is cholesterol.
39 . The amphoteric liposome as claimed in claim 29 , further comprising one or more neutral or zwitterionic amphiphiles.
40 . The amphoteric liposome as claimed in claim 39 , wherein said neutral or zwitterionic lipid is selected from the group consisting of phosphatidylcholines, sphingomyelins, ceramides, phosphatidylethanolamines, cholesterol or mixtures thereof.
41 . The amphoteric liposome as claimed in claim 40 , wherein said neutral or zwitterionic lipids are selected from the group consisting of phosphatidylcholines, sphingomyelins and ceramides, and are present in the lipid mix in an amount of less than 40 mol %.
42 . The amphoteric liposome as claimed in claim 40 , wherein said neutral or zwitterionic lipids are selected from the group consisting of DOPE, cholesterol and a mixture thereof and are present in the lipid mix in an amount of less than 65 mol %.
43 . The amphoteric liposome as claimed in claim 40 , wherein said neutral or zwitterionic lipids are selected from the group consisting of a mixture of phosphatidylcholines (PC), sphingomyelins or ceramides and phosphatidylethanolamines (PE) or a mixture of phosphatidylcholines (PC), sphingomyelins or ceramides and cholesterol (Chol); and said mix of neutral lipids is present in the lipid mix in an amount of not more than 80 mol %.
44 . An amphoteric liposome formulated according to the method as claimed in claim 23 , wherein said liposome comprises a lipid mixture other than one having one of the following specific combinations of amphiphiles:
Cationic
Anionic
amphiphile
amphiphile
Other
Ratio (mol. %)
DOTAP
Chems
30:40
DOTAP
Chems
POPC
10:40:50
DOTAP
Chems
POPC
25:25:50
DOTAP
Chems
POPC
20:30:50
DOTAP
Chems
POPC
20:20:60
DOTAP
Chems
POPC
10:30:60
DOTAP
Chems
POPC
15:25:60
DOTAP
Chems
POPC:N-
10:30:50:10
glutaryl-DPPE
DOTAP
Chems
DPPC:Chol
10:30:50:10
DOTAP
Chems
DPPC
10:30:60
DOTAP
Chems
DPPC
15:35:50
DOTAP
Chems
POPC:Chol
10:20:30:40
DOTAP
Chems
DMPC:Chol
10:30:20:40
DOTAP
Chems
POPC
15:45:40
DOTAP
Chems
POPC
20:60:20
DOTAP
Chems
25:75
DOTAP
Chems
POPC
40:40:20
DOTAP
Chems
POPC
30:50:20
DOTAP
Chems
POPC
10:70:20
DOTAP
Chems
POPC
28:47:25
DOTAP
Chems
DOPE
40:40:20
DOTAP
Chems
DOPE
30:50:20
DOTAP
Chems
DOPE
20:60:20
DOTAP
Chems
DOPE
10:70:20
CHIM
Chems
DPPC
15:35:50
CHIM
Chems
POPC
15:35:50
DC-Chol
DOPA
66:34
DC-Chol
DOPA
Chol
40:20:40
DC-Chol
DOPA
DMPC
27:13:60
DC-Chol
DOPA
DMPC:Chol
27:13:20:40
DC-Chol
DOPA
DMPC:Chol
20:10:30:40
DC-Chol
DOPA
DMPC:Chol
13:7:40:40
HisChol
DG-Succ
DMPC:Chol
10:10:40:40
MoChol
DG-Succ
DMPC:Chol
10:15:35:40
MoChol
DG-Succ
DMPC:Chol
10:10:40:40
MoChol
DG-Succ
DMPC:Chol
10:30:20:40
MoChol
DG-Succ
DPPC:Chol
10:30:20:40
MoChol
DG-Succ
POPC:Chol
10:15:35:40
MoChol
DG-Succ
POPC:Chol
10:30:20:40
MoChol
DG-Succ
POPC:Chol
20:10:30:40
CHIM
DMG-Succ
POPC:DOPE
17:33:12.5:37.5
CHIM
DMG-Succ
POPC:DOPE
33:17:12.5:37.5
CHIM
DMG-Succ
POPC:DOPE
23:47:7.5:22.5
CHIM
DMG-Succ
POPC:DOPE
47:23:7.5:22.5
CHIM
Chems
POPC:DOPE
17:33:12.5:37.5
CHIM
Chems
POPC:DOPE
33:17:12.5:37.5
CHIM
Chems
POPC:DOPE
23:47:7.5:22.5
CHIM
Chems
POPC:DOPE
47:23:7.5:22.5
MoChol
Cetyl-P
POPC:DOPE
20:10:10:60
MoChol
Cetyl-P
POPC:Chol
20:10:35:35
MoChol
DOG-Succ
POPC:DOPE
17:33:12.5:37.5
MoChol
DOG-Succ
POPC:DOPE
33:17:12.5:37.5
MoChol
DOG-Succ
POPC:DOPE
23:47:7.5:22.5
MoChol
DOG-Succ
POPC:DOPE
47:23:7.5:22.5
45 . The amphoteric liposome as claimed in claim 1 , wherein said liposome encapsulates at least one active agent.
46 . The amphoteric liposome as claimed in claim 45 , wherein said active agent is a nucleic acid.
47 . A pharmaceutical composition comprising the active agent-loaded amphoteric liposome as claimed in claim 60 and a pharmaceutical acceptable vehicle therefor.
48 . A method of loading the amphoteric liposome as claimed in claim 1 with a negatively charged cargo moiety, said method comprising acidifying said liposome to said first pH with a first solvent comprising anionic counterions, mixing said liposome with said negatively charged cargo moiety and thereafter elevating the pH of said liposome to said second pH using a second solvent comprising said cationic counterions.
49 . The method as claimed in claim 48 , wherein said acidifying and pH elevating steps are performed by the one-step admixture of the respective solvents, such that said liposome is rapidly brought to the desired respective pH.
50 . The method as claimed in claim 48 , wherein said second pH is about pH 7.4.
51 . The method as claimed in claim 48 , wherein said first pH is in the range of about pH 2 to 5.
52 . The method as claimed in claim 48 , wherein said first solvent comprises a counter-anion having a molecular volume of >50 A 3 for the encapsulation of said cargo moiety at said first pH.
53 . The method as claimed in claim 52 , wherein said counter-anion is selected from the group consisting of citrate, pyrophosphate, barbituric acid and methyl sulphate.
54 . The method as claimed in claim 48 , wherein said cargo moiety comprises a nucleic acid.
55 . A method of predicting the fusogenicity of an amphoteric liposome at a given pH, said liposome being composed of a lipid mixture comprising an anionic amphiphile, a cationic amphiphile, each of said anionic and cationic amphiphiles having respective polar head and apolar tail groups, and optionally one or more neutral amphiphiles, at least one of said anionic and cationic amphiphiles being chargeable; said method comprising:
calculating the κ values for each of said anionic and cationic amphiphiles, when uncharged and when charged and associated respectively with predetermined cationic and anionic counterions for said anionic and cationic amphiphiles respectively, and said one or more optional neutral amphiphiles and the κ salt value for a lipid salt comprising said anionic and cationic amphiphiles in charged form, κ being the ratio of the molecular volume of the polar head group V head to the molecular volume of the apolar tail group V apolar of the respective species, the molecular volumes of the polar head groups of the charged anionic and cationic amphiphiles including the respective counterions, κ salt being defined as: κ salt = V head ( cat ) + V head ( an ) V apolar ( cat ) + V apolar ( an ) wherein V head (cat) is the molecular volume of the polar head group of the cationic amphiphile without the respective counter-anion, V head (an) is the molecular volume of the polar head group of the anionic amphiphile without the respective counter-cation, V apolar (cat) is the molecular volume of the apolar tail group of the cationic amphiphile and V apolar (an) is the molecular volume of the apolar tail group of the anionic amphiphile; and modelling the function κ total (PH) for a lipid mixture of said anionic and cationic amphiphiles and said one or more optional neutral amphiphiles, assuming said cationic and anionic amphiphiles form said lipid salt when charged, κ total (pH) being defined as: κ total ( pH ) = κ an · c an ( pH ) + κ cat · c cat ( pH ) + κ an - · c an - ( pH ) + κ cat + · c cat + ( pH ) + κ salt · c salt ( pH ) + ∑ κ n · c n wherein c an (pH), c cat (pH), C an− (pH), c cat+ (pH) and c salt (pH) are the respective concentrations in the lipid mixture of the uncharged anionic, uncharged cationic, charged anionic and charged cationic amphiphiles and said lipid salt as a function of pH, c n is the concentration in the lipid mixture of the or each optional neutral amphiphile, and κ an , κ cat , κ an e, κ cat+ , κ salt and κ n are the respective K values for the uncharged anionic, uncharged cationic, charged anionic and charged cationic amphiphiles, said lipid salt and the or each optional neutral amphiphile, κ total (pH) being an indicator of the fusogenicity of said liposome.
56 . The method as claimed in claim 55 , wherein said molecular volumes are calculated by molecular modelling.Join the waitlist — get patent alerts
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