GB2065659A - Calciumphosphatidylchlorine- chloride, process for producing the same and pharmaceutical preparations containing the same - Google Patents
Calciumphosphatidylchlorine- chloride, process for producing the same and pharmaceutical preparations containing the same Download PDFInfo
- Publication number
- GB2065659A GB2065659A GB8040311A GB8040311A GB2065659A GB 2065659 A GB2065659 A GB 2065659A GB 8040311 A GB8040311 A GB 8040311A GB 8040311 A GB8040311 A GB 8040311A GB 2065659 A GB2065659 A GB 2065659A
- Authority
- GB
- United Kingdom
- Prior art keywords
- phosphatidylcholine
- chloride
- calcium
- process according
- same
- 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.)
- Withdrawn
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 8
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims abstract description 38
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 18
- 239000001110 calcium chloride Substances 0.000 claims abstract description 18
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 18
- 239000011575 calcium Substances 0.000 claims abstract description 14
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims 3
- 238000004108 freeze drying Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 13
- 235000010445 lecithin Nutrition 0.000 description 8
- 239000000787 lecithin Substances 0.000 description 8
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 7
- 229940067606 lecithin Drugs 0.000 description 7
- 150000002632 lipids Chemical class 0.000 description 6
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- OZXIZRZFGJZWBF-UHFFFAOYSA-N 1,3,5-trimethyl-2-(2,4,6-trimethylphenoxy)benzene Chemical compound CC1=CC(C)=CC(C)=C1OC1=C(C)C=C(C)C=C1C OZXIZRZFGJZWBF-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- SHOJXDKTYKFBRD-UHFFFAOYSA-N mesityl oxide Natural products CC(C)=CC(C)=O SHOJXDKTYKFBRD-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
- C07F9/106—Adducts, complexes, salts of phosphatides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
The present invention provides the new compound calcium phosphatidylcholine chloride as well as a process for producing the same wherein phosphatidylcholine and calcium chloride are reacted in a suitable solvent e.g. an aliphatic alcohol or water and pharmaceutical preparations containing the same.
Description
SPECIFICATION
Calcium phosphatidylcholine chloride, process for producing the same and pharmaceutical preparations containing the same
The present invention is directed to a solid, freeflowing calcium phosphatidylcholine chloride product of high purity which may be readily converted to pharmaceutical preparations. The present invention is further directed to processes for the production of this product and pharmaceutical preparations containing the same.
Lecithin products are phosphorus containing lipids which occur widely in living subject matter as well as in plants. In view of their high physiological importance in various processes of human life, the lecithins have been used for many years in the food industry.
Lecithin products as currently marketed represent a mixture of various components comprising about 35% of oil, phosphatidyl ethanolamine, phosphatidy
Icholine, phosphatidylinosite, phosphatidic acid, phosphatidylserine, sterines and other lipids (see for instance Seifen-Ole-Fette-Wachse 1973, vol. 99/6, p.168 to 169). However, only phosphatidylcholine is therapeutically interesting and important from a nutritive physiological point of view (see H. Peters "Phosphatidylcholine", Spring-Verlag 1976).
Phosphatidylcholine is recovered on a large scale as follows:
Oil is at first extracted from lecithin containing products by means of acetone. The fraction which is insolubie in acetone thereafter is extracted with ethanol and the extracts are purified by adsorption chromatography. The eluate then is evaporated giving substantially pure phosphatidylcholine.
However, the phosphatidylcholine produced in this manner shows some considerable disadvantages. It is obtained as plastic material which has low stability and is difficult to further process and handle.
Therefore, various efforts have been made to convert this plastic material into a free flowing powder or a liquid of low viscosity by the addition of various auxiliary agents. For instance, proteins have been added (see Japanese Patents Nos. 59/8884 and 62/12401 and USP 2 632 705) or mono- or polysaccharides have been used (see USP 2430 553, 2 057 695 and 3 012 888). All these auxiliary agents however have the disadvantage that they either have to be added in large amounts up to 60% or that they are not acceptable physiologically and therefore cannot be used in pharmaceutical preparations. A further disadvantage of the above process is the use of acetone because acidic phosphatides may cause acetone to form condensation products such as mesityloxide or diacetone alcohol.Phosphatidylcholine obtained according to the above process is contaminated with such condensation products which are not only undesired organoleptically but also have a high toxicity even in small amounts and therefore have to be removed. This purification causes additional costs and work.
It is furthermore known (see German Patent 510 186 and Swiss Patents 127256 and 136 239) that the usual lecithin addition product produced with calcium chloride is recovered as a solid pulervizable product by mixing an alcoholic solution of lecithin with an alcohoiic solution of calcium chloride, treating the resulting solution with acetone and separating the precipitated addition compound from the solution and drying it. This process starts with the usual lecithin product which besides phosphatidy
Icholine further contains all other phosphatides such as phosphatidylethanolamine, phosphatidylserine, phosphatidylinosite and other accompanying lipids.
There is obtained by this process therefore an addition compound of this phospholipid mixture with calcium chloride.
According to investigations of H. Hauser and
R.M.C. Dafson (see European Journal of Biochemistry 1967, vol. 1, p.63) the affinity of the calcium ions does not exist for all phospholipids but the calcium ions are only bound by the acid phospholipids such as phosphatidic acid, phosphatidylserine, phosphatidylinosite and further accompanying lipids but not to non-acidic lipids such as phosphatidylcholine. The affinity of calcium ions to phosphatidic acid, phosphatidylserine and phosphatidylinosite is used for instance for the removal of such undesired accompanying lipids from lecithin (see USP 3 081 320).
Based on these test results, it must be regarded as impossible to produce useful calcium chloride addition products with pure phosphatidylcholine.
It now has been found that, surprisingly in view of the above, there may be obtained a stable solid calcium phosphatidylcholine chloride of high purity by dissolving phosphatidylcholine in a suitable solvent and adding thereto a solution of calcium chloride in particular proportions and drying the resulting solution in the usual manner. There are obtained particularly favourable results by using an alcohol as solvent both for the phosphatidylcholine and for the calcium chloride, in particular a lower aliphatic alcohol, and by removing the alcohol without the addition of acetone from the resulting solution. A most preferred solvent is ethanol.The amount of calcium chloride added to the phosphatidylcholine is chosen such that the molar ratio of phosphatidylcholine to calcium chloride is between 1:0.5 and 1:2 and preferably 1:0.5, i.e. that 0.5 to 2 moles of calcium chloride are subjected to reaction with each mole of phosphatidylcholine. It is technically preferred to effect drying by means of a drum evaporator or in a spraydrying tower. Afurther advantage of the present process is that water or aqueous alcohol may be used as solvent in place of the aliphatic alcohol by emulsifying the phosphatidylcholine in an aqueous solution of calcium chloride and subjecting the resulting emulsion directly to drying in a spraydrying tower or to lyophiiisation.
The new calcium phosphatidylcholine chloride which is produced by the present process furthermore may be processed more readily than pure phosphatidylcholine. It is a powder or granular product characterized by a high stability and may be readily used for pharmaceutical preparations in view of its high phosphatidylcholine content. The product may be ground, if necessary, to the desired particle size. If desired, the powder or granular product may be compressed into tablets with the addition of usual galenic additives or may be filled into capsules.
There may also be produced stable injection solutions by emulsifying the product in water. A further advantage of the product produced according to the present process is the absence of any acetone reaction products since of course acetone is not used during its preparation and, if such a reaction product was present in the starting material, any reaction product of acetone is separated from the calcium phosphatidylcholine chloride in the present process during the drying step.
The present invention is further illustrated by the following examples without however limiting the same thereto.
Example I
8 kg (10 moles) of phosphatidylcholine and 1.1 kg (10 moles) of CaCI2 are dissolved with stirring in 4500 cc. of ethanol. Ethanol is separated from the resulting solution by means of a drum dryer. The drying conditions are 1200C and 0.05 bar. There is obtained a slighly yellow flaky product which is ground in a hollow mill or a hammer mill to the desired grain size.
Analysis: P 3.49%; N 1.50% Ca 4.42%; Cl 7.55%.
After dissolving the product in chloroform and evaporating the solvent, the product shows unchanged analytical data.
The product is readily soluble in chloroform, may be dissolved with difficulty only in benzene, is insoluble in petroleum ether, ether and acetone and may be readily emulsified in water.
Example 2
8 kg (10 moles) of phosphatidylcholine and 0.55 kg (5 moles) of calcium chloride are dissolved in 3000 cc. of ethanol and the resulting mixture is further processed as described in Example 1.
Analysis: P 3.59%; N 1.70%; Ca 2.30%; CI 4.02%.
Example 3
8 kg (10 moles) of phosphatidylcholine are emulsified in a solution of 1.1 kg (10 moles) of calcium chloride in 20,000 cc. of water and the resulting emulsion is spray dried in a spraydrying tower at 220 C. There is obtained a slightly yellow powder.
Example 4
8 kg (10 mols) of phosphatidylcholine and 0.55 kg.
(5 moles) of calcium chloride are emulsified in 20,000 cc. of water and further processed as described in Example 3.
Example 5
The product obtained according to Example 2 is ground in a hollow mill, sieved (mesh size 0.5 mm), thoroughly mixed with 1% of Aerosil (finely powderous silicic acid with 99.9% ofSiO2 for adsorption purposes prepared by the German company Degussa AG of Frankfurt/Main, Federal Republic of Germany) and 2% of magnesium stearate and filled into capsules.
Example 6
100 g of calcium phosphatidylcholine chloride are emulsified in 900 cc. of water. The resulting solution issterilised and filled into ampoules to obtain a 10% injection solution. If desired, vitamins and other trace products may be added to the injection solution.
Claims (13)
1. Calcium phosphatidylcholine chloride.
2. Calcium phosphatidylcholine chloride having the formula [PC]. [CaC121, wherein PC is a phosphatidylcholine and xis a number from 0.5 to 2.
3. Calcium phosphatidylcholine chloride according to claim 1 which is obtained by subjecting phosphatidylcholine and calcium chloride to reaction in a suitble solvent and evaporating the resulting solution.
4. Calcium phosphatidylcholine chloride according to claim 3 wherein the phosphatidylcholine and calcium chloride are subjected to reaction in a molar proportion of 0.5 to 2 moles of calcium chloride per each mole of phosphatidylcholine.
5. Process according to claim 4 wherein the reaction is carried out in a suitable sovent and the resulting solution or emulsion is subjected to evaporation.
6. Process according to claim 5 wherein the solvent used is an aliphatic alcohol.
7. Process according to claim 6 wherein the solvent used is ethanol.
8. Process according to claim 5 wherein the solvent used is water.
9. Process according to any of claims 5 to 8 wherein phosphatidylcholine and calcium chloride are subjected to reaction in a molar ratio of 1 to 0.5.
10. Process according to any of claims 5 to 9 wherein evaporation is effected with a drum evaporator.
11. Process according to any of claims 5 to 9 wherein evaporation is effected by spraydrying.
12. Process according to any of claims 5 to 9 wherein drying is effected to lyophilisation.
13. Pharmaceutical preparations comprising a calcium phosphatidylcholine chloride according to any of claims 1 to 4 or produced by the process of any of claims 5 to 12.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2951681 | 1979-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2065659A true GB2065659A (en) | 1981-07-01 |
Family
ID=6089244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8040311A Withdrawn GB2065659A (en) | 1979-12-21 | 1980-12-17 | Calciumphosphatidylchlorine- chloride, process for producing the same and pharmaceutical preparations containing the same |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2065659A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
| US6638495B2 (en) | 1997-09-29 | 2003-10-28 | Nektar Therapeutics | Stabilized preparation for use in metered dose inhalers |
| US7368102B2 (en) | 2001-12-19 | 2008-05-06 | Nektar Therapeutics | Pulmonary delivery of aminoglycosides |
| US7442388B2 (en) * | 2000-05-10 | 2008-10-28 | Weers Jeffry G | Phospholipid-based powders for drug delivery |
| US7871598B1 (en) * | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| US8404217B2 (en) | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
| US9554993B2 (en) | 1997-09-29 | 2017-01-31 | Novartis Ag | Pulmonary delivery particles comprising an active agent |
-
1980
- 1980-12-17 GB GB8040311A patent/GB2065659A/en not_active Withdrawn
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8168223B1 (en) | 1997-09-29 | 2012-05-01 | Novartis Pharma Ag | Engineered particles and methods of use |
| US6638495B2 (en) | 1997-09-29 | 2003-10-28 | Nektar Therapeutics | Stabilized preparation for use in metered dose inhalers |
| US7306787B2 (en) | 1997-09-29 | 2007-12-11 | Nektar Therapeutics | Engineered particles and methods of use |
| US9554993B2 (en) | 1997-09-29 | 2017-01-31 | Novartis Ag | Pulmonary delivery particles comprising an active agent |
| US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
| US8709484B2 (en) | 2000-05-10 | 2014-04-29 | Novartis Ag | Phospholipid-based powders for drug delivery |
| US20110082076A1 (en) * | 2000-05-10 | 2011-04-07 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| US7871598B1 (en) * | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| US8404217B2 (en) | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
| US7442388B2 (en) * | 2000-05-10 | 2008-10-28 | Weers Jeffry G | Phospholipid-based powders for drug delivery |
| US8877162B2 (en) | 2000-05-10 | 2014-11-04 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery |
| US9439862B2 (en) | 2000-05-10 | 2016-09-13 | Novartis Ag | Phospholipid-based powders for drug delivery |
| US8715623B2 (en) | 2001-12-19 | 2014-05-06 | Novartis Ag | Pulmonary delivery of aminoglycoside |
| US9421166B2 (en) | 2001-12-19 | 2016-08-23 | Novartis Ag | Pulmonary delivery of aminoglycoside |
| US7368102B2 (en) | 2001-12-19 | 2008-05-06 | Nektar Therapeutics | Pulmonary delivery of aminoglycosides |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |