WO1991009616A1 - Antibiotiques a la quinolone encapsules dans des vesicules de lipides - Google Patents
Antibiotiques a la quinolone encapsules dans des vesicules de lipides Download PDFInfo
- Publication number
- WO1991009616A1 WO1991009616A1 PCT/US1990/007614 US9007614W WO9109616A1 WO 1991009616 A1 WO1991009616 A1 WO 1991009616A1 US 9007614 W US9007614 W US 9007614W WO 9109616 A1 WO9109616 A1 WO 9109616A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lipid
- lipid vesicle
- quinolone antibiotic
- vesicle
- phospholipid
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention is directed to antibiotic compositions and, more specifically, to antibiotic compositions comprising quinolone antibiotics encapsulated in lipid vesicles.
- the quinolone antibiotics constitute a class of antibiotics that is effective against a large number of microorganisms. In order to be effective, an antibiotic must be present where the microorganisms reside. Therefore, the medium in which a drug is administered can be of considerable importance in determining the efficacy of the drug.
- mycobacteria and bacteria of the genus Salmonella reside in mononuclear phagocytes.
- the presence of high concentrations of antibiotics in mononuclear phagocytes infected with mycobacteria and Salmonella would improve the treatment of diseases caused by these pathogens.
- diseases include ycobacterium aviu intracellulare and salmonellosis, which frequently affect patients with AIDS.
- Quinolone antibiotics are known to be effective against mycobacteria and Salmonella. Nevertheless, such antibiotics do not effectively concentrate in cells that act as hosts for these pathogens.
- Liposomes which can be defined as microscopic structures consisting of one or more concentric lipid bilayers enclosing an equal number of aqueous compartments, are known to concentrate in mononuclear phagocytes. Accordingly, suggestions have been made to encapsulate drugs in liposomes
- SUBSTITUTESHEET in order to target microorganisms that reside in such cells. See, for example. Biotechnology , 850 (1989) .
- compositions capable of killing microorganisms intracellularly comprising an aqueous solution that comprises an effective amount of a quinolone antibiotic encapsulated in a lipid vesicle.
- the quinolone antibiotics useful in the present invention constitute a class of antibiotics that includes as the
- quinolone antibiotic in this specification shall mean any antibiotic having a 4-oxo-l,4-dihydroquinoline moiety.
- Some useful quinolone antibiotics include:
- the preferred quinolone antibiotics include norfloxacin, ciprofloxacin, enoxacin, ofloxacin, and pefloxacin. Ciprofloxacin is especially preferred.
- the quinolone antibiotic is encapsulated in aqueous solution inside a lipid vesicle.
- the lipid used to encapsulate the quinolone antibiotic may be any of the many well known lipids useful for this purpose.
- the lipid will generally comprise a phospholipid, either alone or combined with a sterol or sterol-like molecule such as, for example, cholesterol in a molar ratio of 100:0.1 to 40:60, preferably 100:0.1 to 50:50, more preferably 90:10 to 50:50, and most preferably 60:40 to 50:50.
- the phospholipid may, for example, be phosphatidylcholine (PC) , phosphatidylserine (PS) , phosphatidic acid (PA) , phosphatidylethanolamine (PE) , phosphatidylglycerol (PG) , soybean lecithin (phospholipon 100) and mixtures thereof.
- PC phosphatidylcholine
- PS phosphatidylserine
- PA phosphatidic acid
- PE phosphatidylethanolamine
- PG phosphatidylglycerol
- soybean lecithin soybean lecithin
- Naturally occurring phospholipids such as egg PC and soybean lecithin, are mixtures of phospholipids containing saturated and unsaturated fatty acids.
- Phospholipids comprising saturated fatty acid ester groups are preferred.
- the preferred saturated fatty acid ester groups are palmitoyl and stearoyl ester groups.
- the preferred phospholipids are dipalmitoyl phosphatidylcholine (DPPC) , distearoyl phosphatidylcholine (DSPC) , dipalmitoyl phosphatidylglycerol (DPPG) , distearoylphosphatidylglycerol (DSPG) , mixtures thereof, and mixed esters thereof.
- DPPC dipalmitoyl phosphatidylcholine
- DSPC distearoyl phosphatidylcholine
- DPPG dipalmitoyl phosphatidylglycerol
- DSPG distearoylphosphatidy
- SUBSTITUTESHEET Selection of the most preferred lipid composition for the vesicle requires making a compromise between stability of the vesicle outside the infected cell, which should be high, and stability of the vesicle inside the infected cell, which should be low.
- DSPC is more stable than DPPC both inside and outside cells.
- Mixtures of phospholipids may be used in order to obtain a vesicle having maximal properties such as stability.
- mixtures of DPPC or DSPC and DPPG or DSPG, and especially mixtures of DPPC and DPPG, having a PC:PG molar ratio of approximately 0.5:1 to 20:1, preferably approximately 1:1 to 15:1, and most preferably approximately 7:1 to 10:1 are particularly well suited for use in the present invention.
- Certain components may be added to the lipid membrane for various reasons such as, for example, to impart a charge.
- the presence of phosphatidic acid (PA) , dicetyl phosphate (DCP) , phosphatidyl serine (PS) or phosphatidyl glycerol (PG) in the lipid imparts a negative charge.
- Fatty acid amines, such as stearylamine (SA) impart a positive charge.
- PA, DCP and fatty acid amines may be present in amounts of 0-20 molar percent based on total lipid.
- the concentration of the quinolone antibiotic in aqueous solution inside the lipid vesicle is any concentration that is antibiotically effective when such vesicles enter cells that are infected with microorganisms. Since the vesicles are particularly effective in vivo when administered parenterally, the concentration of the quinolone antibiotic in aqueous solution inside the lipid vesicle is preferably any concentration that is effective _Ln vivo when so administered to a mammal infected with microorganisms that reside in cells.
- the maximum amount of the quinolone antibiotic in aqueous solution inside the lipid vesicle is limited by the solubility of the quinolone antibiotic. The maximum concentration may easily be determined by those skilled in the art.
- lipid vesicles comprising quinolone antibiotics present in an aqueous solution that is at least 10% saturated, preferably at least 50% saturated and, in some cases, more preferably at least 90% saturated with the quinolone antibiotic are suitable in the invention.
- the minimum concentration of the antibiotic in aqueous solution in the lipid vesicle is the minimum concentration that is antibiotically effective when the vesicles enter infected cells such as leukocytes.
- the minimum concentration may easily be determined by those skilled in the art.
- the concentration of the quinolone antibiotic in aqueous solution in the lipid vesicle may be as low as 0.1%, preferably 0.5% and more preferably 1% by weight of a saturated solution.
- the minimum effective concentration of encapsulated quinolone antibiotic in accordance with the invention is generally less than that of unencapsulated quinolone antibiotics. This is because the lipid vesicles concentrate in cells such as in mononuclear phagocytes and other leukocytes where the target microorganisms reside.
- the quinolone antibiotic inside the lipid vesicle is dissolved in water. Due to the low solubility of the quinolone antibiotics, it is preferable for the aqueous solution inside the lipid vesicle to have an acid pH.
- the maximum pH of the aqueous solution is 6.0-6.5, preferably 5.5, and more preferably 5.0.
- the minimum pH is 3.5, preferably 4.0, and more preferably 4.5. It is most preferable for the pH range to be between approximately 4.5 and 5.5, and especially approximately 5.
- a pH of approximately 5 may be maintained by means, for example, of a citrate or acetate buffer.
- aqueous solution inside the lipid vesicle may be isotonic.
- An isotonic solution may be prepared by adding NaCl to the solution of quinolone antibiotic until the solution has an osmolarity of approximately 280-320 m osmol/kg, preferably 280-300 m osmol/kg.
- the lipid vesicles of the present invention may be unilamellar, oligolamellar or multilamellar.
- the size of the liposomes vesicles is any size that is suitable for the purpose to which the vesicles are put.
- the vesicles useful for killing microorganisms residing in cells such as mononuclear phagocytes and other leukocytes _____ vitro may suitably be 0.022u - 5u, and more preferably O.O ⁇ u - 2.5u.
- the size of the vesicle is preferably suitable for parenteral administration.
- Some suitable vesicle sizes for parenteral administration to mammals are 0.022u - l.Ou, preferably 0.05u - 0.5u, and more preferably O.lu - 0.5u.
- vesicles having a suitable range of sizes may be obtained by methods known in the art. Such methods include, for example, polycarbonate membrane filtration and liposome dialysis. Such methods are described in Bosworth et al., J. Pharm. Sciences 7_L, 806-812 (1981) and Olson et al., Biochim. Biophys.
- the lipid vesicles may be prepared by methods that are known in the art. One preferred method is that described by Gregoriadis et al. in Liposome Technology, Vol. I, Gregoriadis, ed. , CRC Press, Boca Raton (1984), pages 19-27; Biotechnology g, 979-984 (1984); Biochem. Biophys. Acts 1003. 58-62 (1989); and J. Immunol. 142.
- This method generally involves dehydration of a mixture of a lipid and a solution of the compound to be encapsulated followed by the carefully controlled rehydration of the mixture.
- the resulting vesicles are referred to as dehydration-rehydration vesicles (DRV) .
- DRV dehydration-rehydration vesicles
- Another method for preparing liposomes containing high levels of quinolone antibiotics is the polycarbonate extrusion method, as described by Mayer et al in BBA 858. 161-168 (1986) .
- solutions of quinolone antibiotics in water is used to resuspend a lipid mixture (phospholipids and cholesterol, as discussed above) by known methods, such as vortexing.
- Repeated extrusion under pressure through polycarbonate membranes with pore sizes from, for example, lu - 0.03u results in small, oligo- or unilamilar vesicles containing the quinolone antibiotic, both inside and outside the membrane.
- vesicles may be lyophilized and rehydrated by methods known in the art such as those described below for DRV vesicles.
- concentration of ciprofloxacin in water used to resuspend the lipids is conveniently approximately 90mM.
- a lipid film is prepared.
- Such films may, for example, be prepared by introducing the lipid into a suitable solvent in tubes and evaporating the solvent.
- suitable solvents include, for example, chloroform and chloroform: methyl alcohol (l:lv/v).
- Suitable tubes include glass tubes having a diameter of 13 or 16 mm. The solvent may be removed by, for example, rotary evaporation or a stream of a suitable gas such as nitrogen gas. Additional drying may be accomplished using high vacuum or freeze-drying techniques.
- step 1 the amount of total phospholipid used in step 1 is 16.5u mol. It will be understood that this is merely one convenient amount, and that other amounts are used depending upon the scale desired. The amount of components discussed in the steps below are suitable when 16.5u mol total phospholipid is used in step 1. When other amounts of phospholipid are used, the amounts of the other components are approximately proportional. It will also be understood that other reaction parameters described herein can be replaced by equivalents that are known in the art.
- the operation may be conducted at temperatures between 4°C and 70°C.
- the operation is conveniently conducted at room temperature.
- the operation is conveniently conducted at 45°C.
- the operation is conveniently conducted at 60°C to 70°C.
- the dispersed lipid from step 2 is formed into smaller vesicles by methods that are known in the art. Such methods include, for example, sonication and extrusion methods. When sonication is used, two periods of about 15 minutes each is suitable. When the lipid comprises egg PC, bath sonication at 20°C is preferred. When the lipid comprises DPPC or DSPC, probe sonication at 45°C or 60°C-70°C is preferred. In both cases, the tubes are flushed or exposed continuously to an inert gas such as nitrogen gas during sonication.
- an inert gas such as nitrogen gas during sonication.
- the small vesicles resulting from step 3 may be stored at low temperatures, i.e., 0-5°C. For example, when the vesicles are stored at 4°C, they are stable for approximately 4-52 weeks, depending on the nature of the lipid.
- step 3 When probe sonication is used in step 3, the resulting vesicles are centrifuged to remove titanium metal. Suitable conditions include approximately 3C0g for 10-20 minutes.
- a solution of the quinolone antibiotic is added to the suspension resulting from steps 3 and/or 4. It is convenient to add the same volume of the quinolone antibiotic solution and the lipid suspension. One ml is suitable.
- the pH of the solution is adjusted to maximize the solubility of the quinolone antibiotic. For example, when ciprofloxacin is the antibiotic, a pH of 4-5.5, preferably 4.5-5.0 is suitable.
- the solution may be isotonic.
- the quinolone antibiotic is in the form of an acid salt.
- acid salts include the HC1, HBr, and lactic acid salt.
- the concentration of the antibiotic solution should take into account an increase in the concentration that occurs later (see below, step 7) .
- a 10-fold concentration increase is convenient. Therefore, the concentration of the quinolone antibiotic in step 5 should be approximately 10% of the desired final concentration.
- the final concentration is that of a saturated solution.
- ciprofloxacin has a solubility of approximately 90mM in water at a pH of 4.5-5.0. Therefore, a suitable concentration of ciprofloxacin in step 5 is approximately 8- 9mM.
- step 6 The mixture from step 5 is dried. Drying may, for example, be by vacuum drying, preferably by lyophilizing for approximately 10-20 hours, or by treatment with nitrogen gas. The drying step is continued until at least about 99% of the water is driven off.
- the dried mixture may be stored until needed at this point. It is preferable to store the mixture at cold temperatures under an inert gas.
- lyophilized lipid vesicles containing ciprofloxacin may be stored under nitrogen at temperatures no higher than minus 20°C for extensive periods of time, i.e., 1-2 years.
- the dried mixture from step 6 is rehydrated with water.
- the volume of water is approximately 10% of the volume of the lipid solution used in step 5. Accordingly, if 1 ml of lipid solution is used in step 5, 100 ul water is used in rehydration step 7.
- the rehydration may take place between 5°C and 70°C, depending on the nature of the lipid. For example, a temperature of 45°C is convenient for hydrating lipids comprising DPPC, and 60°C to 70°C is convenient for hydrating lipids comprising DSPC.
- the hydrated mixture is vigorously mixed, preferably vortexed, to cause sufficient
- an isotonic buffer is added to the viscous mixture resulting from step 7.
- 20mM acetate or citrate conveniently buffer the solution at pH 5.
- the resulting material is vigorously mixed, preferably vortexed, and allowed to stand for at least approximately 30 minutes, preferably at 45°C when the lipid comprises DPPC, or at 60°C to 70°C when the lipid comprises DSPC.
- the buffer is made isotonic by adding sufficient sodium chloride to obtain an osmolarity of 280-300 m osmol/kg.
- Entrapped antibiotic may be separated from free antibiotic. Separation is conveniently achieved by methods known in the art, such as centrifugation (described below) , dialysis or gel filtration.
- the lipid vesicles obtained after Step 7 or Step 8 containing entrapped quinolone antibiotic can be centrifuged at about 20,000 rpm for approximately 18 minutes.
- An SW 50.1 centrifuge (Beckman) operated at room temperature is convenient for this step.
- the supernatant is removed, and the pellet is resuspended in 0.5-1.0 ml of buffer by vigorous shaking, preferably vortexing.
- the centrifugation step may be repeated.
- the final pellet may be stored at 4°C by resuspending the vesicles in, for example, 0.5-1.0 ml buffer.
- the vesicles optionally are subjected to one or more treatments for producing a desired range of vesicle sizes as described above.
- the vesicles are suitable for use in the
- the acid solution is preferably buffered at approximately pH 5.
- the lipid vesicles of the present invention may be used to kill microorganisms that reside in cells.
- Such cells include, for example, leukocytes such as mononuclear phagocytes, Kupffer cells and other tissue macrophages.
- microorganisms that reside in such cells include, for example, mycobacteria and bacteria of the genus Salmonella.
- the antibiotic vesicles are effective in vitro and in vivo.
- the antibiotic When used in vitro. the antibiotic is preferably present in a range between 0.05-10ug/ml, preferably 0.1-lOug/ml, and more preferably l-5ug/ml in the medium containing the microorganism or cells infected by the microorganism.
- the lipid vesicles of the invention may also be used in vivo to treat mammals infected with microorganisms that reside in cells. Accordingly, the present invention may be used to treat mammals suffering from mycobacterium avium intracellulare and salmonellosis.
- compositions of the invention are administered to mammals parenterally.
- the preferred dose of quinolone antibiotic is any dose that is effective.
- Some suitable doses are 7- 25ug/kg, preferably 7-20ug/kg, and more preferably 10- 15ug/kg.
- the exact dose may, however, be outside these ranges, and will depend on several variables, such as the type, age and
- SUBSTITUTESHEET condition of the mammal and the nature and severity of the disease being treated. Those skilled in the medical arts will readily be able to determine the exact dose.
- Vesicles containing four different lipid compositions are made in accordance with the methods described above.
- the four different lipid compositions are given in Table 1.
- the vesicles are made using citrate buffer or acetate buffer throughout and isotonic solutions in step 8. Ciprofloxacin was used as the antibiotic at a concentration of 8mM in step 5. The vesicles were washed twice in step 10
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Abstract
Composition ayant le pouvoir d'éliminer des microorganismes de façon intracellulaire comprenant une quantité efficace d'un antibiotique à base de quinolone encapsulé au sein d'une vésicule de lipide.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US45508189A | 1989-12-22 | 1989-12-22 | |
US455,081 | 1989-12-22 | ||
US54609590A | 1990-06-27 | 1990-06-27 | |
US546,095 | 1990-06-27 |
Publications (1)
Publication Number | Publication Date |
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WO1991009616A1 true WO1991009616A1 (fr) | 1991-07-11 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1990/007614 WO1991009616A1 (fr) | 1989-12-22 | 1990-12-21 | Antibiotiques a la quinolone encapsules dans des vesicules de lipides |
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Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0652008A1 (fr) * | 1993-07-23 | 1995-05-10 | The Minister Of National Defence Of Her Majesty's Canadian Government | Ciprofloxacin encapsulé en liposômes |
WO1996026715A1 (fr) * | 1995-02-27 | 1996-09-06 | The University Of British Columbia | Procede de chargement de vesicules de lipides |
WO1996038147A1 (fr) * | 1995-05-31 | 1996-12-05 | Sepracor Inc. | Procedes et compositions servant au traitement d'infections au moyen de (s)-lomefloxacine optiquement pure |
WO1998046287A2 (fr) * | 1997-04-15 | 1998-10-22 | Uroteq Inc. | Administration de medicaments par l'intermediaire d'hydrogels therapeutiques |
ES2127692A1 (es) * | 1996-11-14 | 1999-04-16 | Hipra Lab Sa | Formulacion de enrofloxacina en liposomas y su preparacion. |
US5968548A (en) * | 1996-04-23 | 1999-10-19 | Minister Of National Defence Of Her Majesty's Canadian Government | Use of liposome encapsulated cirprofloxacin as an immunotherapeutic drug |
US5972379A (en) * | 1995-02-14 | 1999-10-26 | Sequus Pharmaceuticals, Inc. | Liposome composition and method for administering a quinolone |
CN1049337C (zh) * | 1996-09-23 | 2000-02-16 | 苏州长征制药厂 | 旋转酶抑制剂的浓缩水溶液 |
WO2000010533A2 (fr) * | 1998-08-18 | 2000-03-02 | Southern Research Institute | Traitement d'infections intracellulaires et compositions a cet effet |
US6916478B2 (en) | 1995-08-04 | 2005-07-12 | University Of Guelph | Vaccines and pharmaceutical compositions using membrane vesicles of microorganisms, and methods for preparing same |
JP2009529015A (ja) * | 2006-03-08 | 2009-08-13 | バイエル・アニマル・ヘルス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | フルオロキノロン類を含有する医薬 |
US9402845B2 (en) | 2005-12-08 | 2016-08-02 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
US10064882B2 (en) | 2007-05-07 | 2018-09-04 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
US10124066B2 (en) | 2012-11-29 | 2018-11-13 | Insmed Incorporated | Stabilized vancomycin formulations |
US10238675B2 (en) | 2014-05-15 | 2019-03-26 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US11571386B2 (en) | 2018-03-30 | 2023-02-07 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
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Cited By (39)
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US6534508B2 (en) | 1991-11-27 | 2003-03-18 | Sepracor Inc. | Methods and compositions for treating infection using optically pure (S)-lomefloxacin |
US6075024A (en) * | 1991-11-27 | 2000-06-13 | Sepracor Inc. | Methods for treating infection using optically pure (S)-lomefloxacin |
US6337339B2 (en) | 1991-11-27 | 2002-01-08 | Sepracor Inc. | Methods and compositions for treating infection using optically pure (S)-lomefloxacin |
EP0652008A1 (fr) * | 1993-07-23 | 1995-05-10 | The Minister Of National Defence Of Her Majesty's Canadian Government | Ciprofloxacin encapsulé en liposômes |
US5972379A (en) * | 1995-02-14 | 1999-10-26 | Sequus Pharmaceuticals, Inc. | Liposome composition and method for administering a quinolone |
US5800833A (en) * | 1995-02-27 | 1998-09-01 | University Of British Columbia | Method for loading lipid vesicles |
WO1996026715A1 (fr) * | 1995-02-27 | 1996-09-06 | The University Of British Columbia | Procede de chargement de vesicules de lipides |
WO1996038147A1 (fr) * | 1995-05-31 | 1996-12-05 | Sepracor Inc. | Procedes et compositions servant au traitement d'infections au moyen de (s)-lomefloxacine optiquement pure |
US6916478B2 (en) | 1995-08-04 | 2005-07-12 | University Of Guelph | Vaccines and pharmaceutical compositions using membrane vesicles of microorganisms, and methods for preparing same |
US6475516B2 (en) | 1996-04-12 | 2002-11-05 | Dicosmo Frank | Drug delivery via therapeutic hydrogels |
US6132765A (en) * | 1996-04-12 | 2000-10-17 | Uroteq Inc. | Drug delivery via therapeutic hydrogels |
US6228393B1 (en) | 1996-04-12 | 2001-05-08 | Uroteq, Inc. | Drug delivery via therapeutic hydrogels |
US5968548A (en) * | 1996-04-23 | 1999-10-19 | Minister Of National Defence Of Her Majesty's Canadian Government | Use of liposome encapsulated cirprofloxacin as an immunotherapeutic drug |
CN1049337C (zh) * | 1996-09-23 | 2000-02-16 | 苏州长征制药厂 | 旋转酶抑制剂的浓缩水溶液 |
ES2127692A1 (es) * | 1996-11-14 | 1999-04-16 | Hipra Lab Sa | Formulacion de enrofloxacina en liposomas y su preparacion. |
WO1998046287A3 (fr) * | 1997-04-15 | 1999-02-11 | Univ Toronto | Administration de medicaments par l'intermediaire d'hydrogels therapeutiques |
WO1998046287A2 (fr) * | 1997-04-15 | 1998-10-22 | Uroteq Inc. | Administration de medicaments par l'intermediaire d'hydrogels therapeutiques |
WO2000010533A3 (fr) * | 1998-08-18 | 2000-06-08 | Southern Res Inst | Traitement d'infections intracellulaires et compositions a cet effet |
US6264991B1 (en) | 1998-08-18 | 2001-07-24 | Southern Research Institute | Compositions and methods for treating intracellular infections |
WO2000010533A2 (fr) * | 1998-08-18 | 2000-03-02 | Southern Research Institute | Traitement d'infections intracellulaires et compositions a cet effet |
US9549925B2 (en) | 2005-12-08 | 2017-01-24 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
US9402845B2 (en) | 2005-12-08 | 2016-08-02 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
US9511082B2 (en) | 2005-12-08 | 2016-12-06 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
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US9549939B2 (en) | 2005-12-08 | 2017-01-24 | Insmed Incorporated | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
JP2009529015A (ja) * | 2006-03-08 | 2009-08-13 | バイエル・アニマル・ヘルス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | フルオロキノロン類を含有する医薬 |
US10231925B2 (en) | 2006-03-08 | 2019-03-19 | Bayer Intellectual Property Gmbh | Pharmaceuticals containing fluoroquinolones |
US10064882B2 (en) | 2007-05-07 | 2018-09-04 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
US10124066B2 (en) | 2012-11-29 | 2018-11-13 | Insmed Incorporated | Stabilized vancomycin formulations |
US10471149B2 (en) | 2012-11-29 | 2019-11-12 | Insmed Incorporated | Stabilized vancomycin formulations |
US10251900B2 (en) | 2014-05-15 | 2019-04-09 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US10238675B2 (en) | 2014-05-15 | 2019-03-26 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US10398719B2 (en) | 2014-05-15 | 2019-09-03 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US10588918B2 (en) | 2014-05-15 | 2020-03-17 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US10751355B2 (en) | 2014-05-15 | 2020-08-25 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US10828314B2 (en) | 2014-05-15 | 2020-11-10 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US11395830B2 (en) | 2014-05-15 | 2022-07-26 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US11446318B2 (en) | 2014-05-15 | 2022-09-20 | Insmed Incorporated | Methods for treating pulmonary non-tuberculous mycobacterial infections |
US11571386B2 (en) | 2018-03-30 | 2023-02-07 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
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