ZA200103645B - An inhalation system. - Google Patents
An inhalation system. Download PDFInfo
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- ZA200103645B ZA200103645B ZA200103645A ZA200103645A ZA200103645B ZA 200103645 B ZA200103645 B ZA 200103645B ZA 200103645 A ZA200103645 A ZA 200103645A ZA 200103645 A ZA200103645 A ZA 200103645A ZA 200103645 B ZA200103645 B ZA 200103645B
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- South Africa
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- substance
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- treatment
- bioactive agent
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Description
ia - 3 ™ “WO 00127359 PCT/US99/26858
AN INHALATION SYSTEM
The present invention relates to a system for administering pharmaceuticals by inhalation. More particularly the present invention relates to the use of lipids as part of the system.
The pulmonary system is subject to many disorders. There is a continuing need to treat lung diseases such as pre-cancerous or cancerous conditions, damage caused by tobacco smoke and other environmental insults, inflammations and infections.
The lungs can also be a portal to the body by means of uptake by cells of the lung such as aveolar macrophages or through the lymphatic system. Administration of drugs through the lung portal for systematic treatment can avoid hepatic first pass inactivation and allow for lower doses with fewer side effects.
Lung disease is the number three killer in the United States, responsible for one in seven deaths. Significant lung diseases includes such illnesses as: asthma, lung cancer, chronic obstructive pulmonary disease (COPD, which includes emphysema : and chronic bronchitis), influenza, pneumonia, tuberculosis, respiratory distress } syndrome (RDS), cystic fibrosis, sudden infant death syndrome (SIDS), respiratory synctial virus (RSV), AIDS related lung diseases and sarcoidosis. Every year approximately 335,000 Americans die of lung disease. Lung disease not only causes death, but can result in chronic conditions such as asthma, emphysema and chronic bronchitis. :
In the current treatment of lung disease both injectable and pulmonary (via inhalation) administered drugs are employed. In comparison to injection, the administration of a drug by inhalation to treat lung disease is attractive. Inhalation is a more localized administration of the lung disease.therapeutic and, therefore, can be more effective. Inhalation can be easier to use. In certain instances the therapeutic can be self- administered leading to better patient compliance and reduced cost. Although inhalation of therapeutics appear to be an attractive alternative to injection for treating lung disease, inhalation administration still has several significant disadvantages: (1) due to the immunology of the lung, drugs that are administered by inhalation quickly clear the lung and, therefore, yield short term therapeutic effects. This rapid clearance can result in the drug having to be administered more frequently and, therefore, adversely affecting patient compliance and increasing the risk of side effects; (2) targeted delivery of the drug by inhalation to the site of disease is not possible, and the therapeutic is treated like aforeign particle that is quickly cleared from the lung, and eventually it ends up in the reticuloendethial system; (3) inhalation formulations are susceptible to both chemical and enzymatic in-vivo degradation. This degradation is particularly detrimental to peptide and protein formulations; and (4) due to aggregation and lack of stability, formulations of high molecular weight compounds like peptides and proteins are not effectively administered as aerosols, nebulized sprays or as dry powder formulations.
The present invention can overcome these disadvantages in lung disease inhalation therapy, and more importantly it offers new advantages to inhalation that can enhance the therapeutic index of a currently used inhalation or injectable lung disease drug. The invention can be used for the successful entrapment and delivery of both low and high molecular weight compounds. The present invention provides for lipid- containing bioactive agents which can be administered by inhalation as part of a delivery system.
A system for administering a bioactive compound by inhalation having: (a) a composition comprising the biologically-active compound and a . lipid mixture; and ®) an inhalation delivery device; wherein the lipid mixture comprises: 9) a first mixture comprising phosphatidylcholine, negatively- charged lipid, and sterol in the molar ratio of 1-20:1-10:0.5-5; 2) a second mixture comprising phosphatidylcholine, negatively-charged lipid and albumin in the molar ratio of 1-20:1-10:0.1-10; 3) a third mixture comprising phosphatidylcholine, positively-charged lipid and phosphatidylethanolamine in the molar ratio of 1-20:0.5- 20:1-10;
} I © WO 00/27359 PCT/US99/26858 B (4) afourth lipid mixture having phosphatidylcholines: negatively-charged lipids: phosphatidylethanolamines in the molar ratio of 1-20:1-10:1- 10; (5) afifth lipid mixture having phosphatidylcholines: positively-charged lipids: albumin compounds in the molar ratio of 1-20:0.5-20:0.1-10; : or (6) asixth lipid mixture having phosphatidylcholines: positively-charged lipids: sterol compounds in the molar ratio of 1-20:0.5-20:0.5-5. wherein the bioactive agent lipid mixture weight ratio is from 10:1 to 1:500.
The present invention also includes the system wherein the lipid mixture includes: @) phosphatidylcholines: negatively-charged lipids: sterol compounds: phosphatidylethanolamines of the molar ratios 1-20:1-10:0.5-5:1-10; (ii) phosphatidylcholines: negatively-charged lipids: sterol compounds: albumin compounds in the molar ratio of 1-20:1-10:0.5-5:0.1-10; (iii) phosphatidylcholines: negatively-charged lipids: sterol compounds: phosphatidylethanolamines: albumin compounds in the molar ratio of 1- . . 20:1-10:0.5-5:1-10:0.1-10; u 20 (iv) phosphatidylcholines: negatively-charged lipids: albumin ] compounds: sterol compounds in the molar ratio of 1-20:1-10:0.1-10:0.5-5; (v) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: sterol compounds in the molar ratio of 1-20:0.5-20:1- 10:0.5-5; (vi) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: albumin compounds in the molar ratio of 1-20:0.5-20:1- 10:0.1-10; (vii) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: sterol compounds: albumin compounds in the molar ratio o0f1-20:0.5-20:1-10:0.5-5:0.1-10; or (viii) phosphatidylcholines: positively-charged lipids: albumin compounds: sterol compounds in the molar ratio of 1-20:0.5-20:0.1-10:0.5-5.
The present invention includes a method wherein the system is employed for the treatment of a medical condition.
This invention is an inhalation system for the administration of compositions having lipids and bioactive agents and its use in the treatment of diseases, particularly lung disease. The compositions can include liposomes, lipid complexes, lipid clathrates and proliposomes, i.e., compositions which can form liposomes in vitro or in vivo when contacted with water. Compositions are preferably adopted for use by inhalation, and more preferably for use in an inhalation delivery device for the composition’s administration. The inhalation system can be used for the treatment of diseases in both man and animal, particularly lung disease.
The terms “bioactive agent” and “biologically-active” are used interchangeably throughout the specification to describe materials, such as therapeutic, diagnostic and imaging agents, which exhibit biological activity or which can be used for imaging or diagnostic purposes, and which can be administered to living organisms, especially animals such as mammals, particularly humans. Bioactive agents include, but are not limited to: vitamins, hormones, antimetabolites and antimicrobial agents, such as ) antifungal agents, including polyene antifungals, antibacterial agents, including aminoglycosides, antiviral agents and antiparasitic agents. Bioactive agents also include proteins, peptides, ribo- and deoxyribonucleic acids, nucleotides, nucleosides, oligonucleotides, antihistaminic agents and neuropharmacologic agents, including sedatives. Bivdtive digerits further iiclide steroidal and nonsteroidal anti-inflammatory agents, diuretic agents, antihypertensive agents, anti-arrthythmic agents, immunogens, immunomodulators, contraceptive agents, antiviral agents, vascular dilating agents, salicylic acid, resorcinol, phenol, retinoic acid, benzodiazepines, antipyretic agents, antispasmodics, anti-pruritic agents, sympathomimetics, decongestants, tranquilizers, anti-spasmodics, anti-emetics, sedatives and hypnotics, steroidal agents, progestational agents, local anesthetics and desensitizing agents, for example antigens and vaccines.
Bioactive agents include vitamins, nutrients, such as amino acids, essential fats and minerals, retinoids and anti-neoplastic agents, including the anthracyclines and certain alkylating agents. Bioactive agents also include radiocontrast agents, such as the i ™ 6 WO 00127359 PCT/US99/26858 iodinated radiocontrast agents, for example, iotrolan, NMR contrast agents, . radioisotopes, radiolabels and dyes. The above-listed group of bioactive agents, among other agents, including their pharmaceutically acceptable salts, are contemplated for use in the present invention. Determination of compatibilities of the above listed agents with, and the amounts to be utilized in, compositions of the present invention are within the purview of the ordinarily skilled artisan to determine given the teachings of this invention.
The lipids used in the compositions of the present invention can be synthetic, semi-synthetic or naturally-occurring lipids, including phospholipids, tocopherols, sterols, fatty acids, glycoproteins such as albumin, negatively-charged lipids and cationic lipids. In terms of phosholipids, they could include such lipids as egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), phosphatidylethanolamine (EPE), and phosphatidic ’ 15 acid (EPA); the soya counterparts, soy phosphatidylcholine (SPC); SPG, SPS, SPI, SPE, and SPA; the hydrogenated egg and soya counterparts (e.g., HEPC, HSPC), other : phospholipids made up of ester linkages of fatty acids in the 2 and 3 of glycerol positioms : containing chains of 12 to 26 carbon atoms and different head groups in the 1 position of } glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as the : corresponding phosphatidic acids. The chains on these fatty acids can be saturated or unsaturated, and the phospholipid may be made up of fatty acids of different chain lengths and different degrees of unsaturation. In particular, the compositions of the formulations can include DPPC, a major constituent of naturally-occurring lung surfactant. Other examples include dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) distearoylphosphatidylcholine (DSPC) and distearoylphosphatidylglycerol (DSPG), dioleylphosphatidyl-ethanolamine (DOPE) and mixed phospholipids like palmitoylstearoylphosphatidyl-choline (PSPC) and palmitoylstearolphosphatidylglycerol (PSPG), and single acylated phospholipids like mono-oleoyl-phosphatidylethanolamine (MOPE).
The sterols can include, 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, salts of ergosterol including ergosterol hydrogen sulfate and ergosterol sulfate, lanosterol, esters of lanosterol including lanosterol hemi-succinate, salts of lanosterol including lanosterol hydrogen sulfate and lanosterol sulfate. The tocopherols can 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.
The cationic lipids used can include ammonium salts of fatty acids, phospholids and glycerides. The fatty acids include fatty acids of carbon chain lengths of 12 to 26 carbon atoms that are either saturated or unsaturated. Some specific examples include: myristylamine, palmitylamine, laurylamine and stearylamine, dilauroy! ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP) and distearoy! ethylphosphocholine (DSEP), N-(2, 3- di- (9-(Z)-octadecenyloxy)-prop-1-yl-N, N, N-trimethylammonium chloride (DOTMA) and 1, 2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP).
The negatively-charged lipids which can be used include phosphatidyl-glycerols : (PGs), phosphatidic acids (PAs), phosphatidylinositols (PIs) and the phosphatidyl serines oo (PSs). Examples include DMPG, DPPG, DSPG, DMPA, DPPA, DSPA, DMPI, DPPI,
DSPI, DMPS, DPPS and DSPS.
Phosphatidylcholines, such as DPPC, aid in the uptake by the cells in the lung (e.g., the alveolar macrophages) and helps to sustain release of the bioactive agent in the lung. The negatively charged lipids such as the PGs, PAs, PSs and PIs, in addition to reducing particle aggregation, are believed to play a role in the sustained release characteristics of the inhalation formulation as well as in the transport of the formulation across the lung (transcytosis) for systemic uptake. The sterol compounds are believed to affect the release characteristics of the formulation. The mole ratio of the lipids present in the lipid mixtures of the compositions of the present invention are: 1. a first lipid mixture having phosphatidylcholines: negatively-charged lipids: sterol compounds in the molar ratio of 1-20:1-10:0.5-5;
4 ™ “WO 00/27359 PCT/US99/26858 2. a second lipid mixture having phosphatidylcholines: negatively-charged lipids: albumin compounds in the molar ratio of 1-20:1-10:0.1-10; 3. a third lipid mixture having phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines in the molar ratio of 1-20:0.5-20:1-10; 4. a fourth lipid mixture having phosphatidylcholines: negatively-charged lipids: phosphatidylethanolamines in the molar ratio of 1-20:1-10:1-10; 5. a fifth lipid mixture having phosphatidylcholines: positively-charged lipids: albumin compounds in the molar ratio of 1-20:0.5-20:0.1-10; or 6. a sixth lipid mixture having phosphatidylcholines: positively-charged lipids: sterol compounds in the molar ratio of 1-20:0.5-20:0.5-5.
Lipid mixtures of the present invention also include: @) phosphatidylcholines: negatively-charged lipids: sterol compounds: phosphatidylethanolamines of the molar ratios 1-20:1-10:0.5-5:1-10; : 15 (ii) phosphatidylcholines: negatively-charged lipids: sterol compounds: albumin compounds in the molar ratio of 1-20:1-10:0.5-5:0.1-10; (iii) phosphatidylcholines: negatively-charged lipids: sterol compounds: = phosphatidylethanolamines: albumin compounds in the molar ratio of 1-20:1-10:0.5-5:1- . - 10:0.1-10; (iv) phosphatidylcholines: negatively-charged lipids: albumin compounds: sterol compounds in the molar ratio of 1-20:1-10:0.1-10:0.5-5; (v) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: sterol compounds in the molar ratio of 1-20:0.5-20:1- 10:0.5-5; (vi) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: albumin compounds in the molar ratio of 1-20:0.5-20:1- 10:0.1-10; (vii) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: sterol compounds: albumin compounds in the molar ratio of 1-20:0.5-20:1-10:0.5-5:0.1-10; or (viii) phosphatidylcholines: positively-charged lipids: albumin compounds: sterol compounds in the molar ratio of 1-20:0.5-20:0.1-10:0.5-5.
The bioactive agent: lipid mixture weight ratio can vary from 10; 1 to 1 : 500.
The lipid mixtures when combined with bioactive agents are effective in producing formulations that can be used in inhalation device for administration to the lung. The lipids of a class which is present in the lipid mixture can be a single member of the class or two or more members of the class. Thus, for example the phosphatidylcholines can be a single PC such as DPPC or DPPC with one or more other PC’s such as DMPC. The negatively-charged lipids can be PG, PA, PS or PI.
A specific example of lipid mixtures for the composition of the present invention is DPPC : DMPG : cholesterol ata 8.5 : 1.0 : 0.5 mole ratio. Another example can be
DPPC : DMPG : albumin at a molar ratioof 8 : 1 : 2.
Another specific lipid mixture is DPPC : DOPE : DMPG : cholesterol at a mole ratioof 7:4 :3 : 0.5.
In general, PE’s such as DOPE, DMPE, DPPE, DSPE and MOPE can be employed in the lipid mixtures of the present invention.
For lipid mixtures, particularly for use with biologically active compounds of . high molecular weight ( e.g., peptides, proteins, DNA, RNA, genes), a glycoprotein such as albumin or transferrin, referred to as an “albumin compound” can be present. The albumin compounds can be present at a mole ratio of 0.1 to 10 with respect to the other lipids. For example, a lipid mixture can be DPPC : DMPG : albuminina 8: 1 : 2 mole ratio. The albumin can come from either natural , animal (e. g. human or bovine serum albumin) or synthetic sources. Another example of a lipid mixture of the present invention is DOTAP : DPPC : DOPE present in a mole ratio of 2 : 2 : 1. Other examples of a lipid mixture are DPPC : DOTAP : albumin in a molar ratio of 2:2:0.3; and DPPC :
DOTARP : cholesterol in a molar ratio of 8:4:0.5.
The bioactive agents can be a synthetic, semi-synthetic or naturally occurring compounds and include hydrophobic and hydrophilic compounds, compounds of low and high molecular weight (for example from 50 to 100 million Daltons), known drugs, therapeutics, peptides, proteins, DNAs, RNas, genes, and the like.
Claims (1)
- “w' A N “WO 00/27359 PCT/US99/26858 ‘What is claimed:1. A system for administering a bioactive compound by inhalation comprising: (a) a composition comprising the biologically-active compound and a lipid mixture; and (b) an inhalation delivery device; wherein the lipid mixture comprises: ¢)) a first mixture comprising phosphatidylcholine, negatively- charged lipid, and sterol in the molar ratio of 1-20:1-10:0.5-5; 2) a second mixture comprising phosphatidylcholine, negatively-charged lipid and albumin in the molar ratio of 1-20:1-10:0.1-10; 3) a third mixture comprising phosphatidylcholine, positively-charged lipid and phosphatidylethanolamine in the molar ratio of 1-20:0.5- 20:1-10; “) a fourth lipid mixture having phosphatidyicholines: negatively-charged lipids: phosphatidylethanolamines in the molar ratio of 1-20:1-10:1- 10; . 4) a fifth lipid mixture having phosphatidylcholines: positively-charged lipids: albumin compounds in the molar ratio of 1-20:0.5-20:0.1-10; ] or 6) a sixth lipid mixture having phosphatidylcholines: positively-charged lipids: sterol compounds in the molar ratio of 1-20:0.5-20:0.5-5. wherein the bioactive agent lipid mixture weight ratio is from 10:1 to 1:500.2. The system of Claim 1 wherein the lipid mixture comprises: >) phosphatidylcholines: negatively-charged lipids: sterol compounds: phosphatidylethanolamines of the molar ratios 1-20:1-10:0.5-5:1-10; (ii) phosphatidylcholines: negatively-charged lipids: sterol compounds: albumin compounds in the molar ratio of 1-20:1-10:0.5-5:0.1-10; (iii) phosphatidylcholines: negatively-charged lipids: sterol compounds: phosphatidylethanolamines: albumin compounds in the molar ratio of 1- 20:1-10:0.5-5:1-10:0.1-10;(iv) phosphatidylcholines: negatively-charged lipids: albumin compounds: sterol compounds in the molar ratio of 1-20:1-10:0.1-10:0.5-5; (v) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: sterol compounds in the molar ratio of 1-20:0.5-20:1- 10:0.5-5; (vi) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: albumin compounds in the molar ratio of 1-20:0.5-20:1- 10:0.1-10; (vii) phosphatidylcholines: positively-charged lipids: phosphatidylethanolamines: sterol compounds: albumin compounds in the molar ratio of 1-20:0.5-20:1-10:0.5-5:0.1-10; or (viii) phosphatidylcholines: positively-charged lipids: albumin compounds: sterol compounds in the molar ratio of 1-20:0.5-20:0.1-10:0.5-5.3. The system of Claim 1 wherein the negatively-charged lipid is at least one of phosphatidylglycerol, phosphatidic acid or phosphatidylinisotol. 4, The system of Claim 1 wherein the first mixture additionally comprises phosphatidylethanolamine so that the molar ratio of phosphatidylcholine: negatively- i charged lipid: sterol: phosphatidylethanolamine is 1-20:1-3:0.5-5:1-10.5. The system of Claim 3 wherein the first mixture further comprises albumin so that the molar ratio of phosphatidylcholine: negatively-charged lipid: sterol: phosphatidylethanolamine: albumin i§ 1-20:1-5:0.5-5:1- [UU 1-10.6. The system of Claim 1 wherein the first mixture additionally comprises albumin so that the molar ratio of phosphatidylcholine: negatively-charged lipid: sterol: albumin is 1-20:1-5:0.5-5:0.1-10.7. The system of Claim 1 wherein for the first mixture the molar ratio is 5- 10:1-5:0.5-5.Po oe A *'WO0 00/27359 PCT/US99/268588. The system of Claim 7 wherein the negatively-charged lipid is at least one . of phosphatidylglycerol, phosphatidic acid or phosphatidylinisotol.9. The system of Claim 8 wherein the first mixture comprises DPPC: S DPMG: cholesterol: DOPE in the molar ratio of 7:3:0.5:4.10. The system of Claim 1 wherein the second mixture comprises DPPC: DPPG: albumin in a molar ratio of 8:1:2.11. The system of Claim 1 wherein the third mixture comprises DPPC: DOTAP: DOPE in the molar ratio of 2:2:1.12. The system of Claim 1 wherein the second mixture additionally comprises phosphatidylethanolamine so that the molar ratio of phsophatidylcholine: negatively- : 15 charged lipid: albumin: phosphatidlethanolamine is 1-20:1-10:0.1-10:1-10.13. The system of Claim 1 wherein the second mixture further contains sterol so that the molar ratio of phosphatidylcholine: negatively-charged lipid: albumin: SE phosphatidylethanolamine: sterol is 1-20:1-10:0.1-10:1-10:0.5-5.14. The system of Claim 1 wherein the second mixture additionally comprises sterol so that the molar ratio of phosphatidylcholine: negatively-charged lipid: albumin: sterol is 1-20:1-10:0.1-10:0.5-5.15. The system of Claim 1 wherein the third mixture additionally comprises albumin so that the ratio of phosphatidylcholine: positively-charged lipid: phosphatidylethanolamine: albumin is 1-20:0.5-20:1-10:0.1-10.16. The system of Claim 14 wherein the third mixture additionally comprises sterol so that the ratio of phosphatidylcholine: positively-charged lipid: phosphatidylethanolamine: albumin: sterol is 1-20:0.5-20:1-10:0.1-10:0.5-5.PCT/US99/2685817. The system of claim 1 wherein the third mixture additionally comprises sterol so that the ratio of phsophatidylcholine: positively-charged lipid: phosphatidylethanolamine: sterol is 1-20:0.5-20:1-10:0.5-5.18. The system of claim 1 wherein the lipid mixture comprises DPPC : DMPG : cholesterol in a 8.5:1.0:0.5 molar ratio.19. The system of claim 1 wherein the lipid mixture comprises DPPC : DOPE: DMPG: cholesterol in a 7:4:3:0.5 molar ratio.20. The system of claim 1 wherein the lipid mixture comprises DMPC : DMPG : albumin in a 8:1:2 molar ratio.21. The system of claim 20 wherein the bioactive agent is a peptide, protein, DNA, RNA or a gene.22. The system of claim 1 wherein the lipid mixture comprises DOTAP : DPPC : DOPE in a 2:2:1 molar ratio.23. Use of a biologically active compound and a lipid mixture as defined in claim 1 in the manufacture of a medicament for treating a medical condition and which is administrable by inhalation.24. Use of claim 23 wherein the medical condition is cancer.25. Use of claim 24 wherein the bioactive agent is an anthracycline, a platinum compound, a folate antagonist, a pyrimidine antagonist, a purine antagonist, a sugar modified analog, a ribonucleotide reductase inhibitor, a nitrogen mustard compound, an alkane sulfonate, a nitrosourea, a methylating agent, an aziridine, mitoxantrone, a compound affecting endocrine function, a topoisomerase inhibitor, an antibody, a gene, bleomycin, a microtubule inhibitor, a cytokine or a differentiating agent. AMENDED SHEETPCT/US99/2685826. Use of claim 25 wherein the platinum compound is carboplatin or cisplatin.27. Use of claim 25 wherein the topoisomerase inhibitor is a camptothecin.28. Use of claim 25 wherein the differentiating agent is a retinoid.29. Use of claim 25 wherein the gene is the p-53 gene, the p-16 gene, the FHIT gene, and the gene E-cadherin.30. Use of claim 29 wherein the gene is the p-53 gene.31. Use of claim 23 wherein the medical condition is an infection.32. Use of claim 31 wherein the bioactive agent is an anti-infective.33. Use of claim 32 wherein the anti-infective is a sulfonamide, trimethoprim, a quinoline, a beta- lactam, a beta-lactamase inhibitor, an aminoglycoside, a tetracycline, chloramphenicol, a macrolide, clindamycin, a polymyxin or bacitracin.34. Use of claim 33 wherein the bioactive agent is an aminoglycoside.35. Use of claim 34 wherein the aminoglycoside is amikacin.36. Use of claim 34 wherein the aminoglycoside is tobramycin.37. Use of claim 34 wherein the medical condition is a gram negative infection.38. Use of claim 37 wherein the aminoglycoside is amikacin.39. Use of claim 37 wherein the aminoglycoside is tobramycin.40. Use of claim 34 wherein the medical condition is a mycobacterium infection. AMENDED SHEETPCT/US99/2685841. Use of claim 40 wherein the aminoglycoside is amikacin.42. Use of claim 40 wherein the aminoglycoside is tobramycin.43. Use of claim 23 wherein the medical condition is a fungal infection.44. Use of claim 43 wherein the bioactive agent is a polyene antibiotic, flucytosine, an imidazole, a triazole or griseofulvin.45. Use of claim 44 wherein the bioactive agent is a polyene antibiotic.46. Use of claim 45 wherein the bioactive agent is amphotericin B47. Use of claim 45 wherein the bioactive agent is hamycin.48. Use of claim 45 wherein the bioactive agent is nystatin.49. Use of claim 44 wherein the bioactive agent is an imidazole or a triazole.50. Use of claim 49 wherein the bioactive agent is ketoconazole.51. Use of claim 49 wherein the bioactive agent is fluconazole.52. Use of claim 43 wherein the fungal infection is aspergillosis, candidiasis or histoplasmosis.53. Use of claim 23 wherein the medical condition is a viral infection. b4, Use of claim 53 wherein the bioactive agent is antiviral compound.55. Use of claim 54 wherein the bioactive agent is zidovudine, acyclovir, ganciclovir, vidarabine, idoxuridine, trifluridine, an interferon or ribavirin. AMENDED SHEETPCT/US99/2685856. Use of claim 53 wherein the viral infection is AIDS or HIV.57. Use of claim 56 wherein the bioactive agent is zidovudine.58. Use of claim 53 wherein the viral infection is respiratory synctial virus (RSV).59. Use of claim 58 wherein the bioactive agent is ribavirin.60. Use of claim 23 wherein the bioactive agent is an immunosupressive agent.61. Use of claim 60 wherein the immunosupressive agent is cyclosporine, an immune globulin, sulfasazine, methoxsalen or thalidomide.62. Use of claim 23 wherein the bioactive agent is an anticoagulant, antithrombolytic or antiplatelet drug.63. Use of claim 62 wherein the bioactive agent is heparin, coumarin, streptokinase, urikinase, tissue plasminogen activator factor (t-PA), aspirin, dipyrimadole or ticlopidine.64. Use of claim 23 wherein the bioactive compound is a hormone.65. Use of claim 64 wherein the hormone is growth hormone, luetinizing hormone, corticotropin or somatotropin.66. Use of claim 23 wherein the medical condition is diabetes.67. Use of claim 66 wherein the bioactive agent is insulin.68. Use of claim 66 wherein the bioactive agent is glucogon.69. Use of claim 23 wherein the medical condition is osteoprosis, hypercalcemia AMENDED SHEETPCT/US99/26858 or Paget’s Disease.70. Use of claim 69 wherein the bioactive agent is calcitonin.71. Use of claim 69 wherein the bioactive agent is sodium alendronate.72. Use of claim 23 wherein the medical condition is asthma.73. Use of claim 72 wherein the bioactive agent is a methylxanthine, cromolyn, a beta- adrenginic agonist, an anticholinergic alkaloid or an adrenocortical steroid.74. Use of claim 23 wherein the medical condition is chronic obstructive pulmonary disease.75. Use of claim 74 wherein the bioactive agent is methylxanthine, cromolyn; a beta- adrenginic agonist, an anticholinergic alkaloid or an adrenocortical steroid.76. Use of claim 23 wherein the medical condition is cardiovascular disease.77. Use of claim 76 wherein the bioactive agent is an ACE inhibitor, an organonitrate, a calcium channel blocker or a beta adrenegic antagonist.78. Use of claim 23 wherein the medical condition is hypertension.79. Use of claim 78 wherein the bioactive agent is a diuretic, a sympatholytic agent, a vasodilator, a calcium channel blocker or an ACE inhibitor.80. Use of claim 23 wherein the medical condition is cardiac arrhythmia.81. Use of claim 80 wherein the bioactive agent is quinidine, procainamide, lidocaine, encainide, propranolol, esmolol, bretylium, verapimil or diltiazem. AMENDED SHEETPCT/US99/2685882. Use of claim 23 wherein the medical condition is an inflammatory disease.83. Use of claim 82 wherein the bioactive agent is a methylxanthine, cromolyn, a beta-adrenginic agonist, an anticholinergic alkaloid or an adreno cortico-steriod.84. Use of claim 23 wherein the medical condition is pain.8b. Use of claim 84 wherein the bioactive agent is an opioid, meperidine or a congener, methadone or a congener, an opioid antagonist, a centrally active antitussive agent or a cannabinoid.86. Use of claim 85 wherein the bioactive agent is tetrahydrocannabinol.87. Use of claim 23 wherein the medical condition is nausea or vomitting.88. Use of claim 87 wherein the bioactive agent is chloropromazine, prochlorperazine, a cannabinoid, a butyrophenone or a benzamide.89. Use of claim 88 wherein the bioactive agent is a cannabinoid.90. Use of claim 23 wherein the medical condition is smoking addiction.91. Use of claim 90 wherein the bioactive agent is nicotine.92. Use of claim 23 wherein the medical condition is anaphylaxis.93. Use of claim 92 wherein the bioactive agent is adrenaline. 94, Use of claim 23 wherein the medical condition is cystic fibrosis.9b. Use of claim 94 wherein the bioactive agent is DNase, amiloride or CFTRcDNA. AMENDED SHEETPCT/US99/2685896. Use of claim 23 wherein the medical condition is a Pneumocytis carinii infection.97. Use of claim 96 wherein the bioactive agent is pentamidine.98. Use of claim 23 wherein the medical condition is emphysema.99. Use of claim 98 wherein the bioactive agent is alpha-1-antitrypsin or alpha-1- antitrypsin cDNA.100. Use of claim 23 wherein the medical condition is a mycobacterium infection.101. Use of claim 100 wherein the mycobacterium infection is tuberculosis.102. Use of claim 101 wherein the bioactive agent is isoniazid, ethambutol, rifampin and its analogs or an aminoglycoside.103. Use of claim 1 wherein the bioactive agent is a vaccine.104. A substance or composition for use in a method for treating a medical condition, said substance or composition comprising a biologically active compound and a lipid mixture as defined in claim 1, and which is administrable by inhalation, said method comprising administering said substance or composition.105. A substance or composition for us in a method of treatment of claim 104 wherein the medical condition is cancer.106. A substance or composition for use in a method of treatment of claim 105 wherein the bioactive agent is an anthracycline, a platinum compound, a folate antagonist, a pyrimidine antagonist, a purine antagonist, a sugar modified analog, a ribonucleotide reductase inhibitor, a nitrogen mustard compound, an alkane sulfonate, a nitrosourea, a methylating agent, an aziridine, mitoxantrone, a compound affecting endocrine function, a AMENDED SHEETPCT/US99/26858 topoisomerase inhibitor, an antibody, a gene, bleomycin, a microtubule inhibitor, a cytokine or a differentiating agent.107. A substance or composition for use in a method of treatment of claim 106 wherein the platinum compound is carboplatin or cisplatin.108. A substance or composition for use in a method of treatment of claim 106 wherein the topoisomerase inhibitor is a camptothecin.109. A substance or composition for use in a method of treatment of claim 106 wherein the differentiating agent is a retinoid.110. A substance or composition for use in a method of treatment of claim 106 wherein the gene is the p-53 gene, the p-16 gene, the FHIT gene, and the gene E-cadherin.111. A substance or composition for use in a method of treatment of claim 110 wherein the gene is the p-b3 gene.112. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is an infection.113. A substance or composition for use in a method of treatment of claim 112 wherein the bioactive agent is an anti-infective.114. A substance or composition for use in a method of treatment of claim 113 wherein the anti-infective is a sulfonamide, trimethoprim, a quinoline, a beta-lactam, a beta- lactamase inhibitor, an aminoglycoside, a tetracycline, chloramphenicol, a macrolide, clindamycin, a polymyxin ar bacitracin.115. A substance or composition for use in a method of treatment of claim 114 wherein the bioactive agent is an aminoglycoside. AMENDED SHEETPCT/US99/26858116. A substance or composition for use in a method of treatment of claim 115 wherein the aminoglycoside is amikacin.117. A substance or composition for use in a method of treatment of claim 115 wherein the aminoglycoside is tobramycin.118. A substance or composition for use in a method of treatment of claim 115 wherein the medical condition is a gram negative infection.119. A substance or composition for use in a method of treatment of claim 118 wherein the aminoglycoside is amikacin.120. A substance or composition for use in a method of treatment of claim 118 wherein the aminoglycoside is tobramycin.121. A substance or composition for use in a method of treatment of claim 115 wherein the medical condition is a mycobacterium infection.122. A substance or composition for use in a method of treatment of claim 121 wherein the aminoglycoside is amikacin.123. A substance or composition for use in a method of treatment of claim 121 wherein the aminoglycoside is tobramycin.124. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is a fungal infection.125. A substance or composition for use in a method of treatment of claim 124 wherein the bioactive agent is a polyene antibiotic, flucytosine, an imidazole, a triazole or griseofulvin.126. A substance or composition for use in a method of treatment of claim 125 AMENDED SHEETPCT/US99/26858 wherein the bioactive agent is a polyene antibiotic.127. A substance or composition for use in a method of treatment of claim 126 wherein the bioactive agent is amphotericin B128. A substance or composition for use in a method of treatment of claim 126 wherein the bioactive agent is hamycin.129. A substance or composition for use in a method of treatment of claim 126 wherein the bioactive agent is nystatin.130. A substance or composition for use in a method of treatment of claim 125 wherein the bioactive agent is an imidazole or a triazole.131. A substance or composition for use in a method of treatment of claim 130 wherein the bioactive agent is ketoconazole.132. A substance or composition for use in a method of treatment of claim 130 wherein the bioactive agent is fluconazole.133. A substance or composition for use in a method of treatment of claim 124 wherein the fungal infection is aspergillosis, candidiasis or histoplasmosis.134. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is a viral infection.135. A substance or composition for use in a method of treatment of claim 134 wherein the bioactive agent is antiviral compound.136. A substance or composition for use in a method of treatment of claim 135 wherein the bioactive agent is zidovudine, acyclovir, ganciclovir, vidarabine, idoxuridine, trifluridine, an interferon or ribavirin. AMENDED SHEETPCT/US99/26858137. A substance or composition for use in a method of treatment of claim 134 wherein the viral infection is AIDS or HIV.138. A substance or composition for use in a method of treatment of claim 137 wherein the bioactive agent is zidovudine.139. A substance or composition for use in a method of treatment of claim 134 wherein the viral infection is respiratory synctial virus (RSV).140. A substance or composition for use in a method of treatment of claim 139 wherein the bioactive agent is ribavirin.141. A substance or composition for use in a method of treatment of claim 104 wherein the bioactive agent is an immunosupressive agent.142. A substance or composition for use in a method of treatment of claim 141 wherein the immunosupressive agent is cyclosporine, an immune globulin, sulfasazine, methoxsalen or thalidomide.143. A substance or composition for use in a method of treatment of claim 104 wherein the bioactive agent is an anticoagulant, antithrombolytic or antiplatelet drug.144. A substance or composition for use in a method of treatment of claim 143 wherein the bioactive agent is heparin, coumarin, streptokinase, urikinase, tissue plasminogen activator factor (t-PA), aspirin, dipyrimadole or ticlopidine.145. A substance or composition for use in a method of treatment of claim 104 wherein the bioactive compound is a hormone.146. A substance or composition for use in a method of treatment of claim 145 wherein the hormone is growth hormone, luetinizing hormone, corticotropin or somatotropin. AMENDED SHEETPCT/US99/26858147. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is diabetes.148. A substance or composition for use in a method of treatment of claim 147 wherein the bioactive agent is insulin.149. A substance or composition for use in a method of treatment of claim 147 wherein the bioactive agent is glucogon.150. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is osteoprosis, hypercalcemia or Paget's Disease.151. A substance or composition for use in a method of treatment of claim 150 wherein the bioactive agent is calcitonin.152. A substance or composition for use in a method of treatment of claim 150 wherein the bioactive agent is sodium alendronate.153. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is asthma.154. A substance or composition for use in a method of treatment of claim 153 wherein the bioactive agent is a methylxanthine, cromolyn, a beta- adrenginic agonist, an anticholinergic alkaloid or an adrenocortical steroid.155. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is chronic obstructive pulmonary disease.156. A substance or composition for use in a method of treatment of claim 155 wherein the bioactive agent is methylxanthine, cromolyn; a beta- adrenginic agonist, an anticholinergic alkaloid or an adrenocortical steroid. AMENDED SHEETPCT/US99/26858157. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is cardiovascular disease.158. A substance or composition for use in a method of treatment of claim 157 wherein the bioactive agent is an ACE inhibitor, an organonitrate, a calcium channel blocker or a beta adrenegic antagonist.159. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is hypertension.160. A substance or composition for use in a method of treatment of claim 159 wherein the bioactive agent is a diuretic, a sympatholytic agent, a vasodilator, a calcium channel blocker or an ACE inhibitor.161. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is cardiac arrhythmia.162. A substance or composition for use in a method of treatment of claim 161 wherein the bioactive agent is quinidine, procainamide, lidocaine, encainide, propranolol, esmolol, bretylium, verapimil or diltiazem.163. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is an inflammatory disease.164. A substance or composition for use in a method of treatment of claim 163 wherein the bioactive agent is a methylxanthine, cromolyn, a beta-adrenginic agonist, an anticholinergic alkaloid or an adreno cortico-steriod.165. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is pain.166. A substance or composition for use in a method of treatment of claim 165 AMENDED SHEETPCT/US99/26858 wherein the bioactive agent is an opioid, meperidine or a congener, methadone or a congener, an opioid antagonist, a centrally active antitussive agent or a cannabinoid.167. A substance or composition for use in a method of treatment of claim 165 wherein the bioactive agent is tetrahydrocannabinol.168. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is nausea or vomitting.169. A substance or composition for use in a method of treatment of claim 168 wherein the bioactive agent is chloropromazine, prochlorperazine, a cannabinoid, a butyrophenone or a benzamide.170. A substance or composition for use in a method of treatment of claim 169 wherein the bioactive agent is a cannabinoid.171. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is smoking addiction.172. A substance or composition for use in a method of treatment of claim 171 wherein the bioactive agent is nicotine.173. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is anaphylaxis.174. A substance or composition for use in a method of treatment of claim 173 wherein the bioactive agent is adrenaline.175. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is cystic fibrosis.176. A substance or composition for use in a method of treatment of claim 175 AMENDED SHEETPCT/US99/26858 wherein the bioactive agent is DNase, amiloride or CFTRcDNA.177. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is a Pneumocytis carinii infection.178. A substance or composition for use in a method of treatment of claim 177 wherein the bioactive agent is pentamidine.179. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is emphysema.180. A substance or composition for use in a method of treatment of claim 179 wherein the bioactive agent is alpha-1-antitrypsin or alpha-1-antitrypsin cDNA.181. A substance or composition for use in a method of treatment of claim 104 wherein the medical condition is a mycobacterium infection.182. A substance or composition for use in a method of treatment of claim 181 wherein the mycobacterium infection is tuberculosis.183. A substance or composition for use in a method of treatment of claim 182 wherein the bioactive agent is isoniazid, ethambutol, rifampin and its analogs or an aminoglycoside.184. A substance or composition for use in a method of treatment of claim 1 wherein the bioactive agent is a vaccine.185. A system according to claim 1, substantially as herein described and illustrated.186. A substance or composition for use in a method of treatment according to any one of claims 104 to 184, substantially as herein described and illustrated. AMENDED SHEETPCT/US99/26858187. Use according to any one of claims 23 to 103, substantially as herein described and illustrated.188. A new system for administration, a new use of a biologically active compound and a lipid mixture as defined in claim 1, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10812698P | 1998-11-12 | 1998-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200103645B true ZA200103645B (en) | 2002-08-05 |
Family
ID=27733520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200103645A ZA200103645B (en) | 1998-11-12 | 2001-05-04 | An inhalation system. |
Country Status (1)
| Country | Link |
|---|---|
| ZA (1) | ZA200103645B (en) |
-
2001
- 2001-05-04 ZA ZA200103645A patent/ZA200103645B/en unknown
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