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    • 专利摘要:
    Inhalation system and inhalation device of a composition having a lipid and bioactive agent.
    公开号:KR20010111564A
    申请号:KR1020017006029
    申请日:1999-11-12
    公开日:2001-12-19
    发明作者:프랭크 쥐. 필키윅즈
    申请人:프랭크 쥐. 필키윅즈；
    IPC主号:
    专利说明:

    Inhalation System
    [2] There are many diseases associated with the lungs. There is an ongoing need for the treatment of lung diseases such as damage, inflammation and infection due to pre-cancerous or cancerous diseases, smoking and other environmental shocks.
    [3] The lung may be the gateway to the body by absorption through lung cells such as alveolar macrophages or through the lymphatic system. The administration of the drug through the pulmonary barrier for systematic treatment avoids the inactivation caused by the first passage through the liver and enables a low dose with low side effects.
    [4] Pulmonary disease is the third most common cause of death in the United States, which is responsible for one in seven deaths. Major lung diseases include asthma, lung cancer, chronic obstructive pulmonary disease (COPD; including emphysema and chronic bronchitis), influenza, pneumonia, tuberculosis, repiratory distress syndrome (RDS), gallbladder fibrosis, and sudden infant death syndromes (SIDS), respiratory synctial virus (RSV), AIDS-associated pulmonary disease and similar sarcomas. About 335,000 Americans die of lung disease each year. Lung diseases not only cause death, but can also lead to chronic diseases such as asthma, emphysema and chronic bronchitis.
    [5] In the treatment of lung diseases, injection medication and pulmonary medication (via inhalation) are currently used. In treating lung disease, inhalation of the drug is more attractive than injection. Inhalation is a more local dose of pulmonary disease treatment and thus may be more effective. Inhalation is also easier to use. In certain instances, the treatment may be self-dose, resulting in better patient adaptability and lower cost. While inhalation therapy appears to be attractive over injections in the treatment of lung disease, inhalation medication still has some significant disadvantages: (1) Because of the lung's immunity, drugs administered by inhalation are quickly removed from the lung , Shorten the treatment effect. This rapid elimination requires medication to be taken more frequently, thus adversely affecting the patient's adaptability and increasing the risk of side effects; (2) it is not possible to deliver the drug specifically to the affected area by inhalation, the therapeutic drug is treated like a foreign body that is quickly removed from the lungs and eventually terminates in the reticuloendethial system; (3) Inhalation formulations are prone to chemical and enzymatic in vivo degradation. Such degradation is particularly detrimental to peptide and protein preparations; (4) Due to aggregation and lack of stability, high molecular weight compound formulations such as peptides and proteins are not effective for dosing as aerosol, spray or dry powder formulations.
    [6] The present invention can overcome these drawbacks in inhalation therapy of lung disease, and more importantly, provide new benefits to inhalation medications that can enhance the therapeutic index of currently used inhalation or injectable lung disease drugs. do. The present invention can be used to successfully capture and dose both low and high molecular weight compounds. The present invention is also applicable to lipid-containing bioactive agents that can be administered by inhalation as part of a dosage system.
    [1] The present invention relates to a system for administering a drug via inhalation. More specifically, the present invention relates to the use of lipids as part of the system.
    [7] Summary of the Invention
    [8] (a) (1) a first mixture comprising phosphatidylcholine, negatively charged lipids and sterols in a molar ratio of 1-20: 1-10: 0.5-5;
    [9] (2) a second mixture comprising phosphatidylcholine, negatively charged lipids and albumin in a molar ratio of 1-20: 1-10: 0.1-10;
    [10] (3) a third mixture comprising phosphatidylcholine, a positively charged lipid and phosphatidylethanolamine in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10;
    [11] (4) a fourth lipid mixture having a phosphatidylcholine, a negatively charged lipid and a phosphatidylethanolamine in a molar ratio of 1 to 20: 1 to 10: 1 to 10;
    [12] (5) a fifth lipid mixture having a phosphatidylcholine, a positively charged lipid and an albumin compound in a molar ratio of 1-20: 0.5-20: 0.1-10; or
    [13] (6) a sixth lipid mixture having a phosphatidylcholine, a positively charged lipid, a sterol compound in a molar ratio of 1-20: 0.5-20: 0.5-5
    [14] A composition comprising a lipid mixture and a biologically active compound in a weight ratio of 1:10 to 500: 1, and
    [15] (b) suction delivery device
    [16] A system for administering a bioactive compound by inhalation.
    [17] The present invention also provides the lipid mixture
    [18] (i) phosphatidylcholine in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 1 to 10: negatively charged lipids: sterol compound: phosphatidylethanolamine;
    [19] (ii) phosphatidylcholine: negatively charged lipids: sterol compound: albumin compound in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 0.1 to 10;
    [20] (iii) phosphatidylcholine: negatively charged lipids in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 1 to 10: 0.1 to 10: sterol compound: phosphatidylethanolamine: albumin compound;
    [21] (iv) phosphatidylcholine: negatively charged lipids: albumin compound: sterol compound in a molar ratio of 1 to 20: 1 to 10: 0.1 to 10: 0.5 to 5;
    [22] (v) phosphatidylcholine: positively charged lipids: phosphatidylethanolamine: sterol compound in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.5 to 5;
    [23] (vi) phosphatidylcholine in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.1 to 10: positively charged lipids: phosphatidylethanolamine: albumin compound;
    [24] (vii) phosphatidylcholine: positively charged lipids in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.5 to 5: 0.1 to 10: phosphatidylethanolamine: sterol compound: albumin compound; or
    [25] (viii) a system comprising a phosphatidylcholine: positively charged lipid: albumin compound: sterol compound in a molar ratio of 1-20: 0.5-20: 0.1-10: 10.0.5-5.
    [26] The present invention includes a method of using the system in the treatment of a disease.
    [27] <Detailed Description of the Invention>
    [28] The present invention relates to inhalation systems for the administration of compositions with lipids and bioactive agents and their use in the treatment of diseases such as lung diseases in particular. The composition may comprise liposomes, lipid complexes, lipid clathrates and proliposomes (ie, compositions capable of forming liposomes in vivo or ex vivo upon contact with water). The composition is preferably applied for use by inhalation, more preferably in an inhalation delivery device for the administration of the composition. Inhalation systems can be used in both humans and animals, especially for the treatment of lung diseases.
    [29] The terms "bioactive agent" and biological activity, used interchangeably throughout the specification, may be used to indicate biological activity or for imaging or diagnostic purposes, and may be particularly useful in living organisms such as animals, such as mammals (especially humans). Substances such as therapeutic, diagnostic and imaging agents that can be administered are described Bioactive agents include vitamins, hormones, anti-metabolites and anti-microbial agents (antifungal agents including polyene anti-fungal agents, aminoglycosides) Anti-bacterial agents, anti-viral agents and anti-parasitic agents, etc.) Bioactive agents also include proteins, peptides, ribonucleic acids and deoxyribonucleic acids, nucleotides, nucleosides, oligos. Neuropharmacological agents comprising nucleotides, anti-histimins and stabilizers. Non-steroidal anti-inflammatory drugs, diuretics, anti-hypertensives, anti-arrhythmics, immunogens, immunomodulators, contraceptives, anti-virals, vasodilators, salicylic acid, resorcinol, phenol, retinoic acid, benzodiazepines, antipyretics, anti-convulsants, Anti-pruritic agents, sympathetic stimulants, decongestants, sedatives, anti-convulsants, anti-emetics, stabilizers and sleeping pills, steroids, progesterones, local anesthetics and desensitizing agents ( For example, antigens and vaccines.) Bioactive agents include vitamins, nutrients (eg, amino acids, essential fats and minerals), retinoids, and anti-tumor agents (including anthracyclines and certain alkylating agents). The agents also include radiocontrasts, such as iodinated radiocontrasts (eg iotrolans), NMR contrast agents, radioisotopes, radiolabels and dyes. The bioactive agents described (including their pharmaceutically acceptable salts) are intended to be used in the present invention The determination of the compatibility and amount of use of such base agents used with the compositions of the present invention is based upon the teachings of the present invention. It is within the range that can be determined.
    [30] Lipids used in the compositions of the present invention may be synthetic, semi-synthetic or natural lipids and include phospholipids, tocopherols, sterols, fatty acids, glycoproteins (albumins, etc.), negatively charged lipids and cationic lipids. The term phospholipids includes lipids such as egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg phosphatidylethanolamine (EPE) and egg phosphatidic acid (EPA); Soya conterpart (ie soybean phosphatidylcholine (SPC), SPG, SPI, SPS, SPE, SPA); Hydrogenated egg and soybean counterparts (eg HEPC, HSPC); 2 and 3 positions of glycerol containing chains of other 12 to 26 carbon atoms and containing different head groups (choline, glycerol, inositol, serine, ethanolamine and corresponding phosphatidic acid) at 1 position of glycerol And other phospholipids formed from ester bonds of fatty acids. The chains of fatty acids may be saturated or unsaturated, and the phospholipids may be formed from fatty acids of different chain lengths and different degrees of unsaturation. In particular, the composition of the formulation may comprise DPPC which is a major component of the natural waste surfactant. Other examples include dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) dipalmitoylphosphatidylcholine (DPPC) and dipalitoylphosphatidylglycerol (DPPG) distearoylphosphatidylcholine (DSPC) and disdis Theoylylphosphatidylglycerol (DSPG), dioleylphosphatidyl-ethanolamine (DOPE) and mixed phospholipidy-like palmitoylstearoylphosphatidyl-choline (PSPC) and palmitoylstearolphosphatidylglycerol (PSPG) and single acylation Phospholipid-like mono-oleyl-phosphatidylethanolamine (MOPE) and the like.
    [31] Sterols are cholesterol, esters of cholesterol, including cholesterol hemi-succinate, salts of cholesterol, including cholesterol hydrogen sulfate and cholesterol sulfate, ergosterol, esters of ergosterol, including ergosterol hemi-succinate, ergo Salts of ergosterol, including sterol hydrogen sulphate and ergosterol sulphate, esters of lanosterol, including lanosterol, lanosterol hemi-succinate, lanosterol including lanosterol hydrogen sulphate and lanosterol sulfate Salts of sterols. Tocopherols may include tocopherols, esters of tocopherols including tocopherol hemi-succinates, salts of tocopherols including tocopherol hydrogen sulfates and tocopherol sulfates. The term "sterol compound" includes sterols, tocopherols and the like.
    [32] Cationic lipids used may include ammonium salts of fatty acids, phospholipids and glycerides. Fatty acids include saturated or unsaturated fatty acids having a carbon chain length of 12 to 26 carbon atoms. Some specific examples include myristylamine, palmitylamine, laurylamine and stearylamine, dilauryl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine ( DPEP) and distearoyl ethylphosphocholine (DSEP), N- (2,3-di- (9- (Z) -octadecenyloxy) -prop-1-yl-N, N, N- Trimethylammonium chloride (DOTMA) and 1,2-bis (oleyloxy) -3- (trimethylamino) propane (DOTAP).
    [33] The negatively charged lipids that can be used include phosphatidyl-glycerol (PG), phosphatidic acid (PA), phosphatidylinositol (PI) and phosphatidyl serine (PS), for example DMPG, DPPG, DSPG. , DMPA, DPPA, DSPA, DMPI, DPPI, DSPI, DMPS, DPPS and DSPS.
    [34] Phosphatidylcholine, such as DPPC, aids in uptake by cells in the lungs (eg, alveolar macrophages) and helps to sustain release of bioactive agents in the lungs. In addition to reducing particle aggregation, negatively charged lipids such as PGs, PAs, PSs, and PIs play a role in the sustained release properties of inhaled formulations and the delivery of the formulation through the lungs (transcytosis) for systemic absorption. It is believed that Sterol compounds are believed to affect the release properties of the formulation. The molar ratio of lipids present in the lipid mixture of the present compositions is as follows:
    [35] 1. a first lipid mixture having a phosphatidylcholine: negatively charged lipid: sterol compound in a molar ratio of 1-20: 1-10: 0.5-5;
    [36] 2. a second lipid mixture having a phosphatidylcholine: negatively charged lipid: albumin compound in a molar ratio of 1 to 20: 1 to 10: 0.1 to 10;
    [37] 3. a third lipid mixture having a phosphatidylcholine: positive charged lipid: phosphatidylethanolamine in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10;
    [38] 4. fourth lipid mixture having a phosphatidylcholine: negatively charged lipid: phosphatidylethanolamine in a molar ratio of 1 to 20: 1 to 10: 1 to 10;
    [39] 5. a fifth lipid mixture having a phosphatidylcholine: positively charged lipid: albumin compound in a molar ratio of 1 to 20: 0.5 to 20: 0.1 to 10; or
    [40] 6. A sixth lipid mixture having a phosphatidylcholine: positively charged lipid: sterol compound in a molar ratio of 1-20: 0.5-20: 0.5-5.
    [41] Lipid mixtures of the present invention also include:
    [42] (i) phosphatidylcholine in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 1 to 10: negatively charged lipids: sterol compound: phosphatidylethanolamine;
    [43] (ii) phosphatidylcholine: negatively charged lipids: sterol compound: albumin compound in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 0.1 to 10;
    [44] (iii) phosphatidylcholine: negatively charged lipids in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 1 to 10: 0.1 to 10: sterol compound: phosphatidylethanolamine: albumin compound;
    [45] (iv) phosphatidylcholine: negatively charged lipids: albumin compound: sterol compound in a molar ratio of 1 to 20: 1 to 10: 0.1 to 10: 0.5 to 5;
    [46] (v) phosphatidylcholine: positively charged lipids: phosphatidylethanolamine: sterol compound in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.5 to 5;
    [47] (vi) phosphatidylcholine in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.1 to 10: positively charged lipids: phosphatidylethanolamine: albumin compound;
    [48] (vii) phosphatidylcholine: positively charged lipids in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.5 to 5: 0.1 to 10: phosphatidylethanolamine: sterol compound: albumin compound; or
    [49] (viii) phosphatidylcholine: positively charged lipids: albumin compound: sterol compound in a molar ratio of 1 to 20: 0.5 to 20: 0.1 to 10: 0.5 to 5.
    [50] The weight ratio of bioactive agent to lipid mixture can vary from 10: 1 to 1: 500. Lipid mixtures, when mixed with bioactive agents, are effective for preparing formulations that can be used in inhalation devices for pulmonary administration. Any class of lipids present in the lipid mixture may be a single species of that class or a mixture of two or more of those classes. Thus, for example, phosphatidylcholine can be a DPPC having a single PC such as DPPC or one or more other PC classes such as DMPC. The negatively charged lipid may be PG, PA, PS or PI.
    [51] Specific examples of lipid mixtures for the compositions of the present invention include a 8.5: 1.0: 0.5 molar ratio of DPPC: DMPG: cholesterol. Another example may be an 8: 1: 1 molar ratio of DPPC: DMPG: albumin.
    [52] Another specific lipid mixture is a 7: 4: 3: 0.5 molar ratio of DPPC: DOPE: DMPG: cholesterol.
    [53] In general, PEs such as DOPE, DMPE, DPPE, DSPE and MOPE can be used in the lipid mixtures of the present invention.
    [54] In particular, for lipid mixtures for use with high molecular weight bioactive compounds (eg, peptides, proteins, DNA, RNA, genes), glycoproteins such as albumin or transferrin, referred to as "albumin compounds", may be present. have. Albumin compounds may be present in molar ratios of from 0.1 to 10 relative to other lipids. For example, the lipid mixture may be an 8: 1: 1 molar ratio of DPPC: DMPG: albumin. Albumin may be natural or derived from an animal (eg, human or bovine serum albumin) or synthesized. Another example of a lipid mixture of the present invention is DOTAP: DPPC: DOPE present in a 2: 2: 1 molar ratio. Other examples of lipid mixtures include 8: 4: 0.5 molar ratio of DPPC: DOTAP: cholesterol and 2: 2: 0.3 molar ratio of DPPC: DOTAP: albumin.
    [55] Bioactive agents can be synthetic, semi-synthetic or natural compounds, hydrophilic and hydrophobic compounds, low molecular weight and high molecular weight compounds (eg, 50 to 1 million daltons), known drugs, therapeutic agents, peptides, proteins, DANs And RNAs, genes, and the like.
    [56] The present invention includes lipid mixtures in which the molar ratio of any lipid component can be reduced to half its value.
    [57] A "medical disease" is a disease, infection, physical or mental condition, illness, inflammation or other medically-recognized symptom or disorder. Examples of medical conditions include cancer, infections (including but not limited to, bacterial, gram-negative, mycobacterial, fungal, viral, AIDS, HIV and RSV), deficiency in suppressing immune responses, preventing aggregation, Thrombosis or harmful platelet aggregation, hormone deficiency, diabetes, osteoporosis, hypercalcemia, Paget's disease, asthma, COPD, cardiovascular disease, high blood pressure, cardiac arrhythmia, inflammatory disease, pain, nausea, vomiting, smoking poisoning, irritability, gallbladder Fibrosis, Pneumocytyis carnii infection, tuberculosis and emphysema, and the like, but are not limited thereto.
    [58] Liposomes are two layers of fully closed lipid membranes containing entrapped aqueous volumes. Liposomes may be single unilamellar vehicles (with one bilayer membrane) or multiple mutilamellar vehicles (onion-like structures, each characterized by multiple bilayer membranes separated by the next membrane and the aqueous layer). Can be. The bilayer consists of two monolayer lipids with hydrophobic "tail" sites and hydrophilic "head" sites. The structure of the two-layer membrane is a structure in which the hydrophobic (nonpolar) "tails" of the one-layer lipids are oriented towards the center of the two layers, while the hydrophilic "head" is oriented toward the aqueous phase.
    [59] Liposomes can be prepared by a variety of methods (see, for example, Cullis et al. (1987). Bangham's method (J. Mol. Biol. (1965)) is a conventional multiple lamellar vehicle. (MLVs) discloses Lenk et al. (US Pat. Nos. 4,522,803, 5,030,453 and 5,169,637), Fountain et al. (US Pat. Nos. 4,588,578) and Cullis. (US Pat. No. 4,975,282) discloses a process for preparing multiple lamella liposomes having substantially the same lamellae solute distribution in each aqueous compartment US Pat. No. 4,235,871 to Papadjopoulos et al. A method for preparing oligolamellar liposomes by reverse phase evaporation is disclosed.
    [60] Single lamella vehicles can be prepared from MLVs by a number of techniques (e.g., extrusion of Cullis et al. (US Pat. No. 5,008,050) and Loughrey et al. (US Pat. No. 5,059,421)). Sonication and homogenization can be used to produce smaller single lamella liposomes from larger liposomes (eg, Papadzopoulos et al. (1968); Demer and Uster (1983); and Chaff See Chapman et al. (1968).
    [61] The first liposome preparation of Bangam et al. (J. Mol. Biol., 1965, 13: 238-252) entails suspending the phospholipid in an organic solvent and then evaporating to dryness to leave the phospholipid film in the reaction vessel. The appropriate amount of aqueous phase is then added and the 60 mixture is "swelled" and then the resulting liposomes consisting of multiple lamella vehicles (MLV) are dispersed using mechanical means. This preparation provides the basis for the development of sonicated small single lamella vehicles and large single lamella vehicles described in Papadzopoulos et al. (Biochim. Biophys, Acta., 1967, 135: 624-638).
    [62] Liposomes can be prepared using techniques for making large single lamellar vehicles (Luv), such as reversed phase evaporation, injection processes and detergent dilution. An overview of these and other methods for preparing liposomes can be found in Liposomes, Marc Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter 1, the relevant parts of which are referenced herein. Incorporated by reference). See Szoka, Jr. et al. (1980, Ann, Rev. Biophys. Bioeng., 9: 467), the relevant parts of which are incorporated herein by reference.
    [63] Other techniques used to make the vehicle include those forming a reverse phase evaporation vehicle (REV) (US Pat. No. 4,235,871 to Papadzopolos et al.). Another class of liposomes that can be used are those characterized by having substantially the same lamellar solute distribution. This class of liposomes is termed a stable flurimelamela vehicle (SPLV) as defined in US Pat. No. 4,522,803 to Lenk et al., And a single phase vehicle as described in US Pat. No. 4,588,578 to Fountain et al. And as described above. Same frozen and thawed multiple lamellar vehicles (FATMLV).
    [64] Various water soluble derivatives of these, such as sterols and cholesterol hemisuccinate, have been used to form liposomes: in particular US Pat. No. 4,721,612 to Janoff et al., Issued January 26, 1988 (name of invention) , "Steroidal liposomes"), PCT publication WO 85/00968 (Meyhew et al., Published March 4, 1985), which capture drugs in liposomes including alphatocopherol and certain derivatives thereof to reduce their toxicity. Method). In addition, various tocopherols and their water soluble derivatives have been used to form liposomes: PCT Publication No. 87/02219 to Janov et al., Published April 23, 1987 (name of the invention, "alpha tocopherol-based vehicle"). ) Reference.
    [65] In liposome-drug delivery systems, bioactive agents, such as drugs, are administered to a patient to be treated after being captured in liposomes. See, for example, US Pat. No. 3,993,754 to Rahman et al .; US Pat. No. 4,145,410 to Sears et al .; US Pat. No. 4,235,871 to Papadzopoulos et al .; Schneider, US Pat. No. 4,224,179; See US Pat. No. 4,522,803 to Lenk et al. And US Pat. No. 4,588,578 to Fountain et al. Alternatively, if the bioactive agent is lipophilic, the bioactive agent may be associated with the lipid bilayer. In the present invention, the term "capture" is intended to include drugs associated with lipid bilayers and drugs in the aqueous volume of liposomes.
    [66] The size of liposomes is commonly referred to as their diameter and can be measured using a number of techniques well known to those skilled in the art, such as quasi-electric light scattering. In the present invention, liposomes generally have a diameter of about 1 micrometer or more and 5 micrometers or less, preferably 1 micrometer or more and 3 micrometers or less.
    [67] Liposomal sizing can be performed by a number of well-known methods, such as extrusion, sonication and homogenization, and can be readily performed by those skilled in the art. Extrusion involves passing the liposome one or more times under pressure through a filter having a defined pore size. The filter is generally made of polycarbonate, but can be made of any durable material that does not interact with liposomes and is strong enough to allow extrusion under sufficient pressure. Preferred filters include "straight-through" filters that are generally capable of withstanding high pressures for the desired extrusion. "Squiggle path" filters may also be used. Extrusion may use an asymmetric filter, such as a trademark Anotec filter (see US Pat. No. 5,059,421 to Lofrey et al.), Wherein the liposomes are extruded through a branched-pore type aluminum oxide porous filter.
    [68] Acoustic fracturing may also reduce liposome size, where the sonic energy is used to mill or shear the liposomes, and the liposomes spontaneously transform into smaller liposomes. Acoustic fracturing is performed by soaking a glass tube containing a liposome suspension into a sonic epicenter formed in a bad-type sonic shredder. Alternatively, probe type sonic breakers may be used, where sonic energy is generated by the vibration of the titanium probe in direct contact with the liposome suspension. Large liposomes can also be broken into small liposomes using a homogenization and milling device such as a Gilford Wood homogenizer, Polytron ™ or Microfluidizer ™ .
    [69] The resulting liposomes can be separated into uniform populations using methods well known in the art such as tangential flow filtration (see WO 89/00846). In this process, liposomes of non-uniform population size pass through a tangential flow filter, resulting in liposome populations with upper and / or lower limits of size. When using two filters of different sizes with different pore diameters, liposomes smaller than the first pore diameter pass through the filter. The filtered filtrate may be tangential flow filtered through a second filter having a smaller pore size than the first filter. Residues of such filters are liposome populations with upper and lower limits of size defined by the pore sizes of the first and second filters, respectively.
    [70] Meyer et al. May use a transmembrane gradient to mitigate the problems associated with effective liposome capture of ionizable lipophilic bioactive agents such as antitumor agents (eg, anthracycline or vinca alkaloids). The facts were found (see PCT Application No. 86/01102, published February 27, 1986). In addition to causing greater absorption, this dura mater also acts to increase drug retention in liposomes.
    [71] In preliminary human clinical trials with liposomes administered intravenously, liposomes have not been reported to have significant toxicity. Richardson et al. (1979), Br. J. Cancer 40:35; Ryman et al. (1983), “Targeting of Drug”, G. Gregoriadis, et al., Eds. pp 235-248, Plenum, N. Y.]; See Gregoradis G. (1981) Lancet 2: 241 and Lopez-Berestein et al. (1985). Liposomes are reported to be concentrated mainly in reticulum endothelial organs (ie, liver, spleen and bone marrow) that are partitioned by round capillaries and are removed by phagocytes present in these organs.
    [72] The therapeutic properties of many bioactive agents can be dramatically improved when administered in a form captured in liposomes (see, eg, Sheck and Barber (1986)). Toxicity may be reduced compared to drugs in free form, which means that drugs captured with liposomes can be safely administered at high dosages (see, eg, Lopez-Berstein, et al., 1985). Infect. Dis., 151: 701; and Raman et al. (1980), Cancer Res., 40: 1532). The benefits obtained from liposome capture are likely to result from the modified pharmacokinetic properties and biodistribution of the captured drug.
    [73] Many methods can now be used to fill liposomes with bioactive agents (eg, US Pat. No. 3,993,754 to Raman et al .; US Pat. No. 4,145,410 to Ceals et al. US Pat. No. 4,235,871 to Papadzopolos et al. US Pat. No. 4,522,803 to Lenk et al. And US Pat. No. 4,588,578 to Fountain et al.). Ionizable bioactive agents have been known to accumulate in liposomes in response to imparted protons or ion gradients (see, eg, US Pat. No. 5,077,056 to Bally et al .; Meyer et al. (1986); Meyer et al. (1988) And Bali et al. (1988). Liposomal capture can potentially provide a number of beneficial effects on a wide range of bioactive agents, and a high ratio of bioactive agent to lipid has been demonstrated to play an important role in realizing the potential of liposome captured agents.
    [74] The documents incorporated herein are incorporated herein by reference in their contents.
    [75] A "lipid complex" is a conjugate between a bioactive agent and one or more lipids. The bond may be by covalent or ionic bond or by noncovalent interaction. Examples of such complexes include lipid complexes of cardiolipin and amphotericin β that form complexes with doxorubicin.
    [76] A "lipid clathrate" is a three-dimensional structure in cage form that uses one or more lipids whose structure captures bioactive agents.
    [77] "Proliposomes" are agents that can be liposomes when contacted with an aqueous liquid. Agitation or other mixing may be necessary.
    [78] The inhalation delivery device of the inhalation system can be a nebulizer, a metered dose inhaler (MDI) or a dry powder inhaler (DPI). The device can be used to contain and deliver a single dosage of a lipid-mixed bioactive agent composition, or the device can be used to contain and deliver multiple dosages of the composition of the invention.
    [79] Nebulizer type inhalation delivery devices may contain the compositions of the invention in solution (typically aqueous solutions) or suspensions. In order to generate a composition spray for inhalation, the nebulizer type delivery device may be driven by ultrasonic waves, compressed air or other gas, or may be electrically or mechanically driven. Ultrasonic nebulizers typically operate by applying a rapidly vibrating waveform onto the liquid film of the formulation through an electrochemically vibrating surface. At the applied amplitude, the waveform becomes unstable, thereby causing the liquid film to collapse, which creates droplets of the formulation. The nebulizer device, driven by air or other gas, operates based on the fact that the high pressure gas stream produces a local pressure drop that draws the liquid formulation into the gas stream through capillary action. This fine liquid stream is then comminuted by the shear force. The nebulizer can be a hand-held design that can be handled by hand and can be equipped with its own power source. The nebulizer device may consist of a nozzle having two matching discharge channels that have a finite opening size in which the liquid formulation is accelerated. This causes the two streams to collide, resulting in micronization of the formulation. The nebulizer may use a mechanical mover that allows the liquid formulation to pass through a nozzle of multiple openings of defined aperture size to form an aerosol of the formulation for inhalation. In single dose nebulizer designs, blister packs containing a single dose of formulation may be used.
    [80] A metered dose inhaler (MDI) can be used as the inhalation delivery device of the inhalation system. The device is pressurized (pMDI) and its basic construction consists of a metering valve, actuator and container. Propellants are used to release the formulation from the device. The composition may consist of particles of defined size suspended in a pressurized propellant liquid or may be a solution or suspension of a liquid propellant in which the composition is pressurized. Propellants used are primarily environmentally friendly hydrofluorocarbons (HFCs) such as 134a and 227. Conventional chlorofluorocarbons such as CFC-11, 12 and 114 are only used when necessary. The inhalation system device may, for example, deliver a single dose through a blister package or may be a multiple dose design. The pressurized metered dose inhaler of the inhalation system may be breath actuated to deliver the correct dosage of the lipid based formulation. To ensure the accuracy of the dosage, it can be programmed through the microprocessor to allow for delivery of the formulation at a particular point in the inhalation cycle. MDI can be portable, handling by hand.
    [81] Dry powder inhalers (DPIs) can be used as inhalation delivery devices for inhalation systems. The basic design of such a device consists of a metering system, a powdered composition and a method for dispersing the composition. Forces such as rotation and vibration can be used to disperse the composition. The metering and dispensing system can be mechanically or electrically driven and programmed with a microprocessor. The device may be portable that can be handled by hand. The inhaler may be a multiple dose or single dose design and may use conditions such as hard gelatin capsules and blister packaging for accurate unit dose. The composition may be dispersed from the device by passive inhalation (ie, patient's own inhalation effort), or an active dispersing system may be used. The dry powder of the composition can be sized through processes such as jet milling, spray drying and supercritical fluid manufacture. Acceptable excipients such as sugars, mannitol and maltose can be used in the preparation of the powdered formulations. These are particularly important for the preparation of lyophilized liposomes and lipid complexes. These sugars help to maintain the physical properties of liposomes during lyophilization and to minimize the aggregation when they are administered by inhalation. Sugar helps the vehicle maintain its 3-grade hydration state through its hydroxyl group and minimizes the aggregation of particles.
    [82] The three general types of inhalation delivery devices can also be used to deliver the vaccine compositions of the invention.
    [83] Depending on the biological activity of the bioactive agent present in the lipid-living agent composition, the inhalation system of the present invention can be used for the treatment of diseases in a number of therapeutic fields. These therapeutic areas include: infectious diseases (anti-bacterial, anti-fungal and anti-viral activity), inflammatory diseases (including arthritis, and hypertension), neoplastic diseases (cancer), diabetes, osteoporosis, pain treatment And general cardiovascular disease. As discussed above, the inhalation system may be used for the treatment of lung disease. Pulmonary diseases include: asthma, emphysema, lung cancer, chronic obstructive pulmonary disease (COPD), bronchitis, influenza, pneumonia, pulmonary tuberculosis, respiratory distress syndrome, gallbladder fibrosis, childhood sudden death syndrome (SDS), respiratory rash virus (RSV) ), AIDS-associated diseases (e.g., pneumocytis carnie pneumonia, Mycobacterium avium complex, fungal infections, etc.), pseudosarcoma, sleep transient respiratory distress, acute respiratory distress syndrome (ARDS) , Bronchiectasis, bronchiolitis, bronchopulmonary dysplasia, coccidioidomycosis, hantavirus pulmonary disease, histoplasmosis, whooping cough and pulmonary hypertension.
    [84] Some specific examples of the use of such systems in the treatment of biocides and diseases that may be present in the compositions of inhalation systems include: sulfonamides, such as sulfonamides, sulfamemethazoles, and sulfacetamides; Trimethoprine, in particular used in combination with sulfamethoxazole; Quinolines, such as norfloxacin and ciprofloxacin; Beta-lactam compounds, including penicillin such as penicillin G, penicillin V, ampicillin, amoxicillin and piperacillin, cephalosporins such as cephalosporin C, cephalotin, cefacithin and ceftazidime, such as imipenem Other beta-lactam antibiotics, and aztreonam; Beta lactamase inhibitors such as clavulanic acid; Aminoglycosides such as gentamicin, amikacin, tobramycin, neomycin, canthamycin and netylmycin; Tetracyclines such as chlortetracycline and doxycycline; Chloramphenicol; Macrolides such as erythromycin; Or other antibiotics such as clindamycin, polymyxin and bacitracin that are anti-viral and anti-infective in some instances; Polyene antibiotics such as amphotericin B, nystatin and hammycin; Flucitocin; Imidazoles or triazoles such as ketoconazole, myconazole, itraconazole and fluconazole; Glycerofulvin for anti-fungal diseases such as aspergillosis, candidiasis or histoplasmosis; Zidobudine, acyclovir, gancyclovir, vidarabine, idoxiuridine, trifluridine, interferon (eg, interferon alpha-2a or interferon alpha-2b) and ribavirin for anti-viral diseases; Aspirin, phenylbutazone, phenacetin, acetaminophen, ibuprofen, indomethacin, sulindac, pyroxicam, diclofenac; Gold and steroidal anti-inflammatory drugs for inflammatory diseases such as arthritis; ACE inhibitors such as captopril, enalapril and risinopril; Organic nitrates such as amyl nitrite, nitroglycerin and isosorbide dinitrate; Calcium channel blockers such as diltiazem, nifedipine and verapamil, beta adrenergic antagonists such as propranolol for cardiovascular disease; Diuretics such as thiazide; Loop diuretics such as furosemide or benzothiadiazine; Sympathetic inhibitors such as methyldopa, clonidine, guanabenz, guanaethidine and reserpin; Vasodilators such as hydralazine and minoxidil; Calcium channel blockers such as verapimil; ACE inhibitors such as captopril for treating hypertension; Quinoline, procainamide, lidocaine, encinide, propranolol, esmolol, bretyllium, verapimil and diltiazem for the treatment of cardiac arrhythmias; Robostatin, Lipitor, clofibrate, cholestriamine, probutol and nicotinic acid for treating hypolipidemia; Anthracyclines such as doxorubicin, daunorubicin and idarubicin; Platinum compounds such as cisplatin and carboplatin and covalent DNA binding compounds; Folate antagonists such as methotrexate and trimetrexate; Pyrimidine antagonists and anti-metabolites such as fluorouracil, 5-fluorouracil and fluorodeoxyuridine; Purine antagonists and anti-metabolites such as mercaptopurine, 6-mercaptopurine and thioguanine; Sugar modified analogs and anti-metabolites such as cytarabine and fludarabine; Ribonucleotide reductase inhibitors and anti-metabolites such as hydroxyurea; Nitrogen mustard compounds and covalent DNA binding compounds such as cyclophosphamide and ifosfamide; Alkanesulfonates and covalent DNA binding compounds such as busulfan; Nitrosoureas such as carmustine; Methylating agents such as procarbazine and covalent DNA binding compounds; Aziridine and covalent DNA binding compounds such as mitomycin; Non-covalent DNA binding compounds; Non-covalent DNA binding compounds such as mitoxantrone and bleomycin; Topoisomerase inhibitors such as etoposide, teniposide, camptothecin and tocotecan and chromatin function inhibitors; Vinca alkaloids, including vincristine, vinblastine and vindicin, and microtubule inhibitors and chromatin function inhibitors such as paclitaxel, taxotere or other taxanes; Compounds affecting endocrine functions such as antibodies such as prednisone, prednisolone, tamoxifen, leuprolide, ethynyl estradiol, herceftin and the like; genes such as the p-53 gene, p 16 gene, FHIT gene, and gene E-cadherin, interleukins (especially IL-1, IL-2, IL-4, IL-6, IL-8, and IL-12) Cytokines, such as tumor necrosis factor-alpha and tumor necrosis factor-beta, tumor necrosis factor, granulite colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF) and granulosite Colony stimulating factors such as macrophage colony stimulating factor (GM-CSF), interferons such as interferon-alpha, interferon-beta 1, interferon-beta 2 and interferon-gamma; All-trans retinoic acid or other retinoids for cancer treatment; Immunosuppressive agents such as cyclosporin, immunoglobin and sulfazin, methoxsalen and thalidomide; Insulin and glucagon for glucose diseases; Sodium allendronate and calcitonin for the treatment of osteoporosis, hypercalcemia and Paget's disease; Morphine and related opioids; Meperidine or homologue; Methadone or allotropes; Opioid antagonists such as nallopine; Centrally active antitussives such as dextrometophan; Terahydrocannabinol or marinol, lidocaine and bupivacaine for the treatment of pain; Chloropromazine, prochlorperazine; Cannabinoids such as tetrahydrocannabinol, butyrophenones such as dropperidol; Benzamides such as metoclopramide for the treatment of nausea and vomiting; Heparin, comarin, streptokinase, tissue plasminogen activator factor (t-PA) as an anti-coagulant, anti-thrombolytic or anti-platelet drug; Heparin, sulfasalazine, nicotine and corticosteroids for the treatment of inflammatory bowel disease; Nicotine for the treatment of smoking addiction; Growth hormone, luteinizing hormone, corticotropin and somatropin for hormonal therapy; And adrenaline for general hypersensitivity.
    [85] In the case of pulmonary diseases, the use of such systems in the treatment of biocides and diseases that may be present in the compositions of inhalation systems include the following: methylxanthines such as theophylline; Chromoline; Beta-adrenergic agents such as albuterol and tetrabutalin; Anti-cholinergic alkaloids such as atropine and ipartopium bromide; Corticosteroids such as predison, beclomethasone and dexamethasone for asthma or inflammatory diseases; Anti-bacterial and anti-fungal agents described above for anti-bacterial and anti-fungal infections in patients with lung diseases (specific diseases are described above) (especially aminoglycosides {these are for example gram-negative) For the treatment of anti-bacterial infections (eg, in patients with gallbladder fibrosis), for the treatment of Gram-negative infections in patients with tuberculosis, for the treatment of Gram-negative infections in patients with chronic bronchitis and bronchietasis, and generally for immunity Aminoglycosides (amikacin, tobramycin and gentamycin), polymyxins (e.g., polymyxin E, colistin), carboxycillin (ticarcillin) for the treatment of Gram-negative infections in damaged patients; Including monobactam; use of pentamidine for the treatment of patients with pneumocytis carney infection (e.g., HIV / AIDS patients); polyene antibiotics such as amphotericin B, nystine and hamycin of Use; flucitocin; imidazole or triazoles such as ketoconazole, myconazole, itraconazole and fluconazole; treatment of fungal infections (especially occurring or metastasized to the lung), such as asparticosis, candidiasis and histoplasmosis Use of non-steroidal anti-inflammatory drugs for the treatment of anti-inflammatory diseases in patients with corticosteroids and other steroids described above and lung diseases (specific diseases described in lung diseases described above); gallbladder fibrosis CFTRcDNA, DNase, amylolide in the treatment of; alpha-1-antitrypsin and alpha-1-antitrypsin cDNA for the treatment of emphysema; amicacin, tobramycin or gentamicin for the treatment of tuberculosis or mycobacterial infection Aminoglycosides such as isoniazid, ethambutol, rifamipine and their analogues; Anti-cancer agents described above for the treatment of lung cancer, in particular cisplatin, carboplatin, taxanes (eg paclitaxel and taxanes), camptothecin, topotecin and other camptothecins, herceptin, p -53 Gene and Use of IL-2.
    [86] Pharmaceutical formulations of inhalation systems may contain one or more drugs (eg, two drugs that exhibit synergistic effects).
    [87] In addition to the lipids, albumin and drugs discussed above, the compositions of inhalation system pharmaceutical formulations may contain excipients (including solvents, salts and buffers), preservatives and surfactants that are acceptable for inhalation administration in humans or animals.
    [88] The particle size of pharmaceutical formulations developed for use in inhalation systems can vary between 0.5 to 10 micrometers, with the range of 1 to 5 micrometers being most preferred for inhalation. The particle sizes of the formulations may be set prior to filling them into the inhalation delivery device of the inhalation system or, depending on their design, the inhalation delivery device itself may size the size of the particles. The pharmaceutical formulation of the inhalation system may be in powder, liquid or suspension.
    [89] Inhalation systems can also be used for the administration of vaccines. In this case, the vaccine composition consists of the lipids and biologically active antigens discussed above at the molar compositions described. The lipid: antigen molar ratio can be 1,000,000: 1 to 1: 100. The inhalation system consists of a lipid based vaccine formulation and an inhalation delivery device. The vaccine inhalation system can be used for the practical treatment and prevention of the diseases described above (especially lung diseases such as influenza, pneumonia, RSV, tuberculosis, etc.). Particle sizes and methods for their preparation are as discussed above, and vaccine formulations may contain excipients (including solvents, salts and buffers), preservatives and surfactants that are acceptable for inhalation administration to humans or animals. The vaccine formulation may contain one or more antigens.
    [90] The term "treatment" means administering a composition to an animal, such as a mammal or a human, to prevent, alleviate, treat or ameliorate a disease.
    [91] Generally, dosages of bioactive agents will be selected by the physician based on age, physical condition, weight and other factors known in the medical arts. In general, in the case of active agents, the dosage will be within the same range as in the use of the invention with respect to the free drug.
    [92] <Reference for Suction Device>
    [93] 1. Hickey A.J. and Dunbar C.A., “A New Millennium for Inhaler Technology”, Pharmaceutical Technology, pgs. 119-115, June (1997).
    [94] Blood. P. Lioyd et al., “A New Unit Dose, Breath-Actuated Aerosol Drug Delivery System”, in Repiriatory Drug Delivery V, P. R. P.R. Byron, R. N. R.N. Dalby and S.J. Published by S. J. Farr, Interpharm, Press, Buffalo Grove, pgs. 364-366 (1996).
    [95] 3. J. H. J.H. Bell, P.S. Hartley and J. S. Rat. J. S. G. Cox, “Dry Powder Aerosols I: A New Inhalation Device”, J. Pharm. Sci., 60 (10), pgs. 1539-1564 (1971).
    [96] 4. J. Double. Tom and J. W. Tom. Debendetti, "Particle Formation with Supercritical Liquids-A Review", J. Aerosol Sci., 22, pgs. 555-584 (1991).
    [97] 5. M.P. Billings, R.N. Boyes, L. M. L.M. Clisby, A.D. A. Harper, p. P. Braithwaite and S. S. Williams, "Design, Development and Performance of a Novel Multidose Dry Powder Inhaler", Pharmaceutical Technology, pgs. 70-82, October (1999).
    [98] 6. Ogden J., Rogerson C. and Smith I., “Issues in Pulmonary Delivery”, Scripps Magazine, pgs. 56-60, June91997).
    [99] <Other references>
    [100] Forsmeyer F. Possmayer FI, Metcalfe IL and Ehorning G., The Pulmonary Surfactant-Contol of Fluidity at the Air-Liquid Membrane, In Membrane Fluidity, Kate M. Edited by Kates M. and Katis A., pgs. 57-67, Clifton NJ, Humana Press (1980).
    [101] 2. Ligand targeting of liposomes, Leserman L. and Machy P. Liposome from Biophysics to Therapeutics, pgs. 157-194, edited by Ostro M., New York, NY, Marcel Dekker (1987).
    [102] 3. Gonzalez-Rhoti RJ, Casace J., Straub L. and Schreier H. Liposome and Pulmonary Alveolar Macrophages: Functional and Morphologic Interactions, Exp. Lung Res., 17, pgs. 687-705 (1991).
    [103] 4. Geiger K., Gallagher ML, and Hedley-White J., Celluar Distribution and Clearance of Aerosolized Dipalmitoyl Choline, J. Appl. Physiol., 39, pgs. 759-766 (1975).
    [104] 5. Bates S. Phatespholipids Co-Isolated with Rat Protein C account for the Apparent Protein Enhanced Uptake of Liposomes into Lung Granular by Bates SR, Ibach PB and Fisher AB. Pneumocytes, Exp. Lung Res., 15, pgs. 695-708 (1989).
    [105] 6. A. Rat. A.G. Goodman and L. L. Goodman, "The Pharmaceutical Basis of Therapeutics, Eighth Edition", A. Rat. A.G. Goodman, T. Dube. T.W.Rall, A.S. A.S. Nies and P. Edited by P. Taylor, Permagon Press, New York, NY (1990)].
    权利要求:
    Claims (103)
    [1" claim-type="Currently amended] (a) (1) a first mixture comprising phosphatidylcholine, negatively charged lipids and sterols in a molar ratio of 1-20: 1-10: 0.5-5;
    (2) a second mixture comprising phosphatidylcholine, negatively charged lipids and albumin in a molar ratio of 1-20: 1-10: 0.1-10;
    (3) a third mixture comprising phosphatidylcholine, a positively charged lipid and phosphatidylethanolamine in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10;
    (4) a fourth lipid mixture having a phosphatidylcholine, a negatively charged lipid and a phosphatidylethanolamine in a molar ratio of 1 to 20: 1 to 10: 1 to 10;
    (5) a fifth lipid mixture having a phosphatidylcholine, a positively charged lipid and an albumin compound in a molar ratio of 1-20: 0.5-20: 0.1-10; or
    (6) a sixth lipid mixture having a phosphatidylcholine, a positively charged lipid, a sterol compound in a molar ratio of 1-20: 0.5-20: 0.5-5
    A composition comprising a lipid mixture and a biologically active compound in a weight ratio of 1:10 to 500: 1, and
    (b) suction delivery device
    System for administering the bioactive compound by inhalation comprising a.
    [2" claim-type="Currently amended] The method of claim 1 wherein the lipid mixture is
    (i) phosphatidylcholine in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 1 to 10: negatively charged lipids: sterol compound: phosphatidylethanolamine;
    (ii) phosphatidylcholine in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 0.1 to 10: negatively charged lipids: sterol compound: albumin compound
    (iii) phosphatidylcholine: negatively charged lipids in a molar ratio of 1 to 20: 1 to 10: 0.5 to 5: 1 to 10: 0.1 to 10: sterol compound: phosphatidylethanolamine: albumin compound;
    (iv) phosphatidylcholine: negatively charged lipids: albumin compound: sterol compound in a molar ratio of 1 to 20: 1 to 10: 0.1 to 10: 0.5 to 5;
    (v) phosphatidylcholine: positively charged lipids: phosphatidylethanolamine: sterol compound in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.5 to 5;
    (vi) phosphatidylcholine in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.1 to 10: positively charged lipids: phosphatidylethanolamine: albumin compound;
    (vii) phosphatidylcholine: positively charged lipids in a molar ratio of 1 to 20: 0.5 to 20: 1 to 10: 0.5 to 5: 0.1 to 10: phosphatidylethanolamine: sterol compound: albumin compound; or
    (viii) a phosphatidylcholine: positively charged lipid: albumin compound: sterol compound in a molar ratio of 1 to 20: 0.5 to 20: 0.1 to 10: 0.5 to 5.
    [3" claim-type="Currently amended] The system of claim 1, wherein the negatively charged lipid is at least one of phosphatidylglycerol, phosphatidic acid, or phosphatidylinisotol.
    [4" claim-type="Currently amended] The method of claim 1, wherein the first mixture further comprises phosphatidylethanolamine such that the molar ratio of phosphatidylcholine: negatively charged lipid: sterol: phosphatidylethanolamine is 1-20: 1-3: 0.5-5: 1-10. System that includes.
    [5" claim-type="Currently amended] The method of claim 3, wherein the first mixture is such that the molar ratio of phosphatidylcholine: negatively charged lipids: sterol: phosphatidylethanolamine: albumin is from 1 to 20: 1 to 5: 0.5 to 5: 1 to 10: 0.1 to 10. Further comprising albumin.
    [6" claim-type="Currently amended] The method of claim 1, wherein the first mixture further comprises albumin such that the molar ratio of phosphatidylcholine: negatively charged lipid: sterol: albumin is from 1 to 20: 1 to 5: 0.5 to 5: 0.1 to 10. system.
    [7" claim-type="Currently amended] The system of claim 1 wherein the molar ratio of the first mixture is from 5 to 10: 1 to 5: 0.5 to 5.
    [8" claim-type="Currently amended] 8. The system of claim 7, wherein said negatively charged lipid is at least one of phosphatidylglycerol, phosphatidic acid or phosphatidylinisotol.
    [9" claim-type="Currently amended] The system of claim 8, wherein the first mixture comprises DPPC: DPMG: Cholesterol: DOPE in a molar ratio of 7: 3: 0.5: 4.
    [10" claim-type="Currently amended] The system of claim 1, wherein the second mixture comprises DPPC: DPPG: albumin in a molar ratio of 8: 1: 1.
    [11" claim-type="Currently amended] The system of claim 1, wherein the third mixture comprises DPPC: DOTAP: DOPE in a molar ratio of 2: 2: 1.
    [12" claim-type="Currently amended] The method of claim 1, wherein the second mixture further comprises phosphatidylethanolamine such that the molar ratio of phosphatidylcholine: negatively charged lipid: albumin: phosphatidylethanolamine is from 1 to 20: 1 to 10: 0.1 to 10: 1 to 10. System that includes.
    [13" claim-type="Currently amended] The method of claim 1, wherein the second mixture is such that the molar ratio of phosphatidylcholine: negatively charged lipids: albumin: phosphatidylethanolamine: sterol is from 1 to 20: 1 to 10: 0.1 to 10: 1 to 10: 0.5 to 5. Further comprising sterols.
    [14" claim-type="Currently amended] The method of claim 1, wherein the second mixture further comprises sterol such that the molar ratio of phosphatidylcholine: negatively charged lipid: albumin: sterol is 1-20: 1-10: 0.1-10: 0.5-5. system.
    [15" claim-type="Currently amended] The method of claim 1, wherein the second mixture further comprises albumin such that the molar ratio of phosphatidylcholine: positive charged lipid: phosphatidylethanolamine: albumin is from 1 to 20: 0.5 to 20: 1 to 10: 0.1 to 10. System.
    [16" claim-type="Currently amended] 15. The method of claim 14, wherein the third mixture is such that the molar ratio of phosphatidylcholine: positive charged lipids: phosphatidylethanolamine: albumin: sterol is 1-20: 0.5-20: 1-10: 0.1-10: 10: 0.5-5. Further comprising sterols.
    [17" claim-type="Currently amended] The system of claim 1, further comprising sterols such that the molar ratio of phosphatidylcholine: positively charged lipids: phosphatidylethanolamine: sterols is from 1 to 20: 0.5 to 20: 1 to 10: 0.5 to 5.
    [18" claim-type="Currently amended] The system of claim 1, wherein the lipid mixture comprises DPPC: DMPG: Cholesterol in a molar ratio of 8.5: 1.0: 0.5.
    [19" claim-type="Currently amended] The system of claim 1, wherein the lipid mixture comprises DPPC: DOPE: DMPG: Cholesterol in a molar ratio of 7: 4: 3: 0.5.
    [20" claim-type="Currently amended] The system of claim 1, wherein the lipid mixture comprises DMPC: DMPG: Albumin in a molar ratio of 8: 1: 2.
    [21" claim-type="Currently amended] The system of claim 20, wherein the bioactive agent is a peptide, protein, DNA, RNA or gene.
    [22" claim-type="Currently amended] The system of claim 1, wherein the lipid mixture comprises DOTAP: DPPC: DOPE in a molar ratio of 2: 2: 1.
    [23" claim-type="Currently amended] A method of treating a disease comprising using the system of claim 1.
    [24" claim-type="Currently amended] The method of claim 23, wherein the disease is cancer.
    [25" claim-type="Currently amended] The bioactive agent of claim 24 wherein the bioactive agent is anthracycline, platinum compound, folate antagonist, pyrimidine antagonist, purine antagonist, sugar modified analog, ribonucleotide reductase inhibitor, nitrogen mustard compound, alkanesulfonate, nitrosourea , A methylating agent, aziridine, mitoxantrone, a compound that affects endocrine function, a topoisomerase inhibitor, an antibody, a gene, a bleomycin, a microtubule inhibitor, a cytokine or a differentiating agent .
    [26" claim-type="Currently amended] The method of claim 25, wherein said platinum compound is carboplatin or cisplatin.
    [27" claim-type="Currently amended] The method of claim 25, wherein said topoisomerase inhibitor is camptothecin.
    [28" claim-type="Currently amended] 27. The method of claim 25, wherein said diffrentizing agent is a retinoid.
    [29" claim-type="Currently amended] The method of claim 25, wherein said gene is a p-53 gene, p-16 gene, FHIT gene and gene E-cadherin.
    [30" claim-type="Currently amended] The method of claim 29, wherein said gene is a p-53 gene.
    [31" claim-type="Currently amended] The method of claim 23, wherein the disease is an infection.
    [32" claim-type="Currently amended] The method of claim 31, wherein the bioactive agent is an anti-infective agent.
    [33" claim-type="Currently amended] 33. The method of claim 32, wherein the anti-infective agent is sulfonamide, trimethoprine, quinoline, beta-lactam, beta-lactamase inhibitor, aminoglycoside, tetracycline, chloramphenicol, marclide, clindamycin, poly A method of treatment that is mixin or bacitracin.
    [34" claim-type="Currently amended] The method of claim 33, wherein the bioactive agent is aminoglycoside.
    [35" claim-type="Currently amended] The method of claim 34, wherein the aminoglycoside is amikacin.
    [36" claim-type="Currently amended] The method of claim 34, wherein the aminoglycoside is tobramycin.
    [37" claim-type="Currently amended] The method of claim 34, wherein the disease is a Gram negative infection.
    [38" claim-type="Currently amended] The method of claim 37, wherein the aminoglycoside is amikacin.
    [39" claim-type="Currently amended] The method of claim 37, wherein the aminoglycoside is tobramycin.
    [40" claim-type="Currently amended] The method of claim 34, wherein the disease is a mycobacterial infection.
    [41" claim-type="Currently amended] The method of claim 40, wherein the aminoglycoside is amikacin.
    [42" claim-type="Currently amended] The method of claim 40, wherein the amioglycoside is tobramycin.
    [43" claim-type="Currently amended] The method of claim 23, wherein the disease is a fungal infection.
    [44" claim-type="Currently amended] The method of claim 43, wherein the bioactive agent is a polyene antibiotic, flucitocin, imidazole, triazole, or glycerofulbin.
    [45" claim-type="Currently amended] 45. The method of claim 44, wherein the bioactive agent is a polyene antibiotic.
    [46" claim-type="Currently amended] 46. The method of claim 45, wherein the bioactive agent is amphotericin B.
    [47" claim-type="Currently amended] 46. The method of claim 45, wherein the bioactive agent is hamamycin.
    [48" claim-type="Currently amended] 46. The method of claim 45, wherein the bioactive agent is nystatin.
    [49" claim-type="Currently amended] The method of claim 44, wherein the bioactive agent is imidazole or triazole.
    [50" claim-type="Currently amended] The method of claim 49, wherein the bioactive agent is ketoconazole.
    [51" claim-type="Currently amended] The method of claim 49, wherein the bioactive agent is fluconazole.
    [52" claim-type="Currently amended] The method of claim 43, wherein the fungal infection is aspergillosis, candidiasis or histoplasmosis.
    [53" claim-type="Currently amended] The method of claim 23, wherein the disease is a viral infection.
    [54" claim-type="Currently amended] The method of claim 53, wherein the bioactive agent is an anti-viral compound.
    [55" claim-type="Currently amended] The method of claim 54, wherein the bioactive agent is zidovudine, acyclovir, gancyclovir, vidarabine, idoxuridine, trifluridine, interferon or ribavirin.
    [56" claim-type="Currently amended] The method of claim 53, wherein the viral infection is AIDS or HIV.
    [57" claim-type="Currently amended] The method of claim 56, wherein the bioactive agent is zibovudine.
    [58" claim-type="Currently amended] The method of claim 53, wherein the viral infection is respiratory synctial virus (RSV).
    [59" claim-type="Currently amended] The method of claim 53, wherein the bioactive agent is ribavirin.
    [60" claim-type="Currently amended] The method of claim 23, wherein the bioactive agent is an immunosuppressive agent.
    [61" claim-type="Currently amended] 61. The method of claim 60, wherein said immunosuppressive agent is cyclosporin, immunoglobulin, sulfazazine, methoxalene or thalidomide.
    [62" claim-type="Currently amended] The method of claim 23, wherein the bioactive agent is an anti-coagulant, anti-thrombolytic or anti-platelet drug.
    [63" claim-type="Currently amended] 63. The method of claim 62, wherein the bioactive agent is heparin, coumarin, spreptokinase, free kinase, tissue plasminogen activator factor (t-PA), aspirin, dipyrimadol or ticlopidine.
    [64" claim-type="Currently amended] The method of claim 23, wherein the bioactive compound is a hormone.
    [65" claim-type="Currently amended] The method of claim 64, wherein the hormone is a growth hormone, luteinizing hormone, corticotropin or somatotropin.
    [66" claim-type="Currently amended] The method of claim 23, wherein the disease is diabetes.
    [67" claim-type="Currently amended] 67. The method of claim 66, wherein the bioactive agent is insulin.
    [68" claim-type="Currently amended] 67. The method of claim 66, wherein the bioactive agent is glucagon.
    [69" claim-type="Currently amended] The method of claim 23, wherein the disease is osteoporosis, hypercalcemia, or Paget's disease.
    [70" claim-type="Currently amended] The method of claim 69, wherein the bioactive agent is calcitonin.
    [71" claim-type="Currently amended] 70. The method of claim 69, wherein the bioactive agent is sodium allenronate.
    [72" claim-type="Currently amended] The method of claim 23, wherein the disease is asthma.
    [73" claim-type="Currently amended] 74. The method of claim 72, wherein the bioactive agent is methylxanthine, chromoline, beta-adrenergic agonist, anti-cholinergic alkaloid or corticosteroid.
    [74" claim-type="Currently amended] The method of claim 23, wherein the disease is chronic obstructive pulmonary disease.
    [75" claim-type="Currently amended] 75. The method of claim 74, wherein the bioactive agent is methylxanthine, chromoline, beta-adrenergic agonist, anti-cholinergic alkaloid or corticosteroid.
    [76" claim-type="Currently amended] The method of claim 23, wherein the disease is a cardiovascular disease.
    [77" claim-type="Currently amended] The method of claim 76, wherein the bioactive agent is an ACE inhibitor, an organic nitrate, a calcium channel blocker or a beta adrenergic antagonist.
    [78" claim-type="Currently amended] The method of claim 23, wherein the disease is hypertension.
    [79" claim-type="Currently amended] The method of claim 78, wherein the bioactive agent is a diuretic, sympathetic inhibitor, vasodilator, Karlsch channel blocker, or ACE inhibitor.
    [80" claim-type="Currently amended] The method of claim 23, wherein the disease is cardiac arrhythmia.
    [81" claim-type="Currently amended] 81. The method of claim 80, wherein the bioactive agent is quinidine, procainamide, lidocaine, encinide, propanolol, esmolol, brethlium, verapimil or diltiazem.
    [82" claim-type="Currently amended] The method of claim 23, wherein the disease is an inflammatory disease.
    [83" claim-type="Currently amended] 84. The method of claim 82, wherein the bioactive agent is methylxanthine, chromoline, beta-adrenergic agonist, anti-cholinergic alkaloid or corticosteroid.
    [84" claim-type="Currently amended] The method of claim 23, wherein the disease is pain.
    [85" claim-type="Currently amended] 85. The method of claim 84, wherein the bioactive agent is an opioid, meperidine or isoform, methadone or isoform, opioid antagonist, centrally active antitussive or cannabinoid.
    [86" claim-type="Currently amended] 86. The method of claim 85, wherein the bioactive agent is tetrahydrocannabinol.
    [87" claim-type="Currently amended] The method of claim 23, wherein the disease is nausea or vomiting.
    [88" claim-type="Currently amended] 88. The method of claim 87, wherein the bioactive agent is chloropromazine, prochlorperazine, cannabinoids, butyrophenone or benzamide.
    [89" claim-type="Currently amended] 89. The method of claim 88, wherein the bioactive agent is cannabinoid.
    [90" claim-type="Currently amended] The method of claim 23, wherein the disease is smoking addiction.
    [91" claim-type="Currently amended] 91. The method of claim 90, wherein the bioactive agent is nicotine.
    [92" claim-type="Currently amended] The method of claim 23, wherein the disease is hypersensitivity.
    [93" claim-type="Currently amended] 93. The method of claim 92, wherein the bioactive agent is adrenaline.
    [94" claim-type="Currently amended] The method of claim 23, wherein the disease is gallbladder fibrosis.
    [95" claim-type="Currently amended] 95. The method of claim 94, wherein the bioactive agent is DNase, amylolide or CFTRcDNA.
    [96" claim-type="Currently amended] The method of claim 23, wherein the disease is Pneumocystis carinii infection.
    [97" claim-type="Currently amended] 97. The method of claim 96, wherein the bioactive agent is pentamidine.
    [98" claim-type="Currently amended] The treatment method according to claim 23, which is a type of disease.
    [99" claim-type="Currently amended] The method of claim 98, wherein the bioactive agent is alpha-1-antitrypsin or alpha-1-antitrypsin cDNA.
    [100" claim-type="Currently amended] The method of claim 23, wherein the disease is a mycobacterial infection.
    [101" claim-type="Currently amended] 101. The method of claim 100, wherein the mycobacterial infection is tuberculosis.
    [102" claim-type="Currently amended] 102. The method of claim 101, wherein the bioactive agent is isoniazid, etabutol, rifampin and analogs or aminoglycosides thereof.
    [103" claim-type="Currently amended] The method of claim 1, wherein the bioactive agent is a vaccine.
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    同族专利:
    公开号 | 公开日
    NZ511568A|2003-08-29|
    CZ20011581A3|2001-12-12|
    ES2281199T3|2007-09-16|
    MXPA01004828A|2002-09-18|
    EP1128813A4|2004-08-18|
    PL347630A1|2002-04-22|
    AU1621200A|2000-05-29|
    HU0104255A2|2002-03-28|
    IL143046D0|2002-04-21|
    AT353630T|2007-03-15|
    CA2351063A1|2000-05-18|
    DE69935154T2|2007-10-25|
    DE69935154D1|2007-03-29|
    WO2000027359A1|2000-05-18|
    JP2002529393A|2002-09-10|
    EP1128813B1|2007-02-14|
    CN100358494C|2008-01-02|
    EP1128813A1|2001-09-05|
    AU766703B2|2003-10-23|
    CN1332626A|2002-01-23|
    HU0104255A3|2002-12-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-11-12|Priority to US10806798P
    1998-11-12|Priority to US10812698P
    1998-11-12|Priority to US60/108,067
    1998-11-12|Priority to US60/108,126
    1999-11-12|Application filed by 프랭크 쥐. 필키윅즈
    1999-11-12|Priority to PCT/US1999/026858
    2001-12-19|Publication of KR20010111564A
    优先权:
    申请号 | 申请日 | 专利标题
    US10806798P| true| 1998-11-12|1998-11-12|
    US10812698P| true| 1998-11-12|1998-11-12|
    US60/108,067|1998-11-12|
    US60/108,126|1998-11-12|
    PCT/US1999/026858|WO2000027359A1|1998-11-12|1999-11-12|An inhalation system|
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