CN101193622A - Method and composition for treating inflammatory disorders - Google Patents
Method and composition for treating inflammatory disorders Download PDFInfo
- Publication number
- CN101193622A CN101193622A CNA2006800205359A CN200680020535A CN101193622A CN 101193622 A CN101193622 A CN 101193622A CN A2006800205359 A CNA2006800205359 A CN A2006800205359A CN 200680020535 A CN200680020535 A CN 200680020535A CN 101193622 A CN101193622 A CN 101193622A
- Authority
- CN
- China
- Prior art keywords
- compositions
- acid
- recorded
- phospholipid
- buffer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Abstract
There is provided homogeneous pharmaceutical compositions for the treatment of inflammatory disorders comprising an antiinflammatory and/or antihistaminic active ingredient, a polar lipid liposome and a pharmaceutically-acceptable aqueous carrier.
Description
Invention field
The present invention relates to be used for the treatment of the compositions of the method for inflammatory diseases, and preparation method thereof.
Background and prior art
The essence that numerous disease/disorder is arranged is inflammation.The inflammatory diseases that influences the crowd comprises asthma, inflammatory bowel, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
Inflammation also is the common cause of pain.Inflammatory pain can be caused by a lot of reasons, as infecting, performing the operation or other wound.In addition, several diseases comprise malignant tumor and the known inflammatory component with increase patient symptom of cardiovascular disease.
Asthma is to contain inflammation and and the respiratory tract disease of bronchoconstriction composition.The treatment of asthma method is based upon on the basis of disease severity.Light patient need not treat or only treat by sucking the beta-2-agonists that influences the bronchoconstriction composition, yet more serious asthmatic patient is regularly treated by sucking the corticosteroid that is in the nature anti-inflammatory drug to a great extent usually.A kind of new asthma prophylactic treatment, thus it works by the leukotriene of inhibition 5-lipoxygenase blocking-up proinflammatory and the generation of cytokine.
Anaphylaxis and non-allergic rhinitis are common diseases, influence about 30% crowd.Rhinitis has a strong impact on quality of life.In fact, rhinitis be considered to quality of life influence ratio such as asthma is more serious.
Pollinosis and long-term allergic rhinitis are characterised in that sneeze, rhinorrhea, nasal congestion, pruritus, conjunctivitis and pharyngitis.In perennial rhinitis, the chronic nasal obstruction is a cardinal symptom, can develop into eustachian tube obstruction.
Oral or local is first-line treatment to rhinitis with the antihistaminic medicine, and the nasal cavity steroidal is a second line treatment.Concerning Most patients, topical corticosteroid and long-acting hydryllin be relief of symptoms significantly.The antihistaminic medicine also can influence (non-IgE) mediated hypersensitivity on the non-immunology, for example non-allergic rhinitis, the motion asthma, cold urticaria and the non-specific bronchial hyperreactivity that cause.
The main clinical effect of antihistaminic medicine comprises and has reduced sneeze and rhinorrhea.Yet, stop up more insensitive to nasal cavity.The advantage that topical antihistaminic medicine (for example nitrogen Si spit of fland and levocabastine) has comprises rapid-action less with side effect.
Inflammatory pain can alleviate by suppressing cyclooxygenase (COX).The COX enzyme exists with two kinds of forms, a kind of constitutive expression many cells and the tissue in (COX-1), a kind of the inflammatory response phase by the proinflammatory stimulus object, as cytokine induction (COX-2).
It is unstable intermediate PGH that COX makes arachidonic acid metabolic
2(PGH
2).PGH
2Further be metabolised to other prostaglandin, comprise PGE
2, PGF
2 α, PGD
2, prostacyclin and thromboxan A
2Known these arachidonic acid metabolites have significant physiology and pathophysiology activity, comprise the proinflammatory effect.
Especially, known PGE
2Be a kind of strong proinflammatory regulator, and cause fever and pain.Therefore, be conceived to suppress PGE
2Formation researched and developed a lot of medicines, comprise " NSAIDs " (non-steroidal antiinflammatory drugs) and " coxibs " (selective COX-2-inhibitor 2).These drug mains will pass through to suppress COX-1 and/or COX-2, thereby reduce PGE
2Generation work.
Leukotriene (LTs) forms from arachidonic acid by one group of enzyme that is different from the COX/PGES approach.Key enzyme in the leukotriene biosynthesis is 5-lipoxygenase (5-LO), and this enzyme is catalysis LTA in two-step reaction
4Form from arachidonic acid.Leukotriene A
4Can be leukotriene B by further metabolism
4, this reacts by LTA
4Hydrolytic enzyme catalysis.Cell leukotriene biosynthesis depends on 5-lipoxygenase activated protein (FLAP), and this albumen is the embrane-associated protein that combines and promote the reaction of 5-lipoxygenase with arachidonic acid.Known leukotriene B
4Be a kind of strong proinflammatory regulator, and contain the leukotriene C of cysteinyl
4, D
4And E
4(CysLTs) be the extremely strong regulator that causes bronchoconstriction and proinflammatory, this regulator is got involved in the pathology of asthma and inflammation.Therefore, commercial 5-LO inhibitor and the antagonist that contains cysteinyl leukotriene receptor 1 and 2 represented the new anti-inflammatory treatment of two classes, and commercialization FLAP inhibitor, leukotriene A
4Hydrolase inhibitor, leukotriene B
4The exploitation of receptor antagonist can further provide the anti-inflammatory treatment of new classification.
Aspect the related cytoactive of the inflammatory process that occurs in regulating chronic obstruction pneumonopathy (COPD) and asthma, 4 type phosphodiesterases (PDE4) play an important role.On behalf of a class, the PDE4 inhibitor have the novel drugs that suppresses bronchoconstriction and inflammation-inhibiting cytoactive (comprising the generation that suppresses leukotriene) potentiality.
Liposome (being also referred to as lipid carrier) is the micelle by natural origin or the deutero-polar lipid molecule preparation of chemosynthesis.That crooked double-layer of lipoid is formed is this spherical, the structure of sealing, typically is used to seal be generally cytotoxic drug, to reduce toxicity and/or to increase effect.Liposomal encapsulated pharmaceutical preparation provides water solution reconstruct before administration at once then with dry (for example lyophilization) form usually.Do like this to reduce following probability: for example cytotoxic drug dissolves in the aqueous solution and leaks, thereby reduces the influence of sealing of liposome.
Also use liposome and seal various medical compoundss and be used for nasal route and send, to improve bioavailability or as accessory drugs.The medicine that can mention comprises that tetanus toxin vaccine, insulin, Desmopressin and diphenhydramine hydrochloride are (referring to people such as T ü rker, Review Article:Nasal Route and medicine Delivery Systems, Pharm.World Sci., 2004; 26,137-142, and list of references cited herein) and ciprofloxacin, CM3 and albuterol (referring to people such as Desai, A Facile Method ofDelivery of Liposomes by Nebulization, J.Control.Release, 2002; 84,69-78).
In rabbit model, liposomal encapsulated cetirizine is absorbed (people such as Elzainy to estimate periphery anti-histamine activity and whole body by topical, Cetirizine from TopicalPhosphatidylcholine-Hydrogenated Liposomes, The AAPS Journal, 2004; 6,1-7 is also referring to Drug Development and Industrial Pharmacy, 2005; 31,281-291).
The pharmaceutical composition that contains the homogenizing of alerlisin and polar lipid liposome discloses in International Patent Application WO 2005/107711.
Also in the liposome system of phosphatidylcholine aqueous buffer solution, studied alerlisin the lipophilic behavior (people such as Plemper van Balen G., Lipophilicity behaviour of thezwistterionic antihistamine cetirizine in phosphatidylcholine liposomes/watersystems, Pharm.Res.2001; 18,694-701).
Comprise especially other formulation examples such as US 4,427,649, the US5 of the active component of liposome, 569,464, EP 0249561, WO 00/38681, US 4,839,175 and WO 98/00111 be described.
We are surprised to find, and relevant with some antiinflammatory of administration and/or anti-histamine activity composition usually (for example nose) stimulates and can alleviate by the pharmaceutical composition that uses homogenizing, and said composition comprises these active component, polar lipid liposome and pharmaceutically suitable carrier.
The invention provides the pharmaceutical composition of the homogenizing that is suitable for treating inflammatory diseases, comprise antiinflammatory and/or anti-histamine activity composition, polar lipid liposome and pharmaceutically acceptable aqueous carrier, condition is that active component is not an alerlisin, hereinafter compositions is called " present composition ".
Those of ordinary skill in the art should be appreciated that antiinflammatory and/or the anti-histamine activity composition (vide infra) that uses medicine effective quantity in the present composition.Term " medicine effective quantity " refers to that the patient that can treat expects the amount of antiinflammatory and/or anti-histamine activity composition of therapeutic effect, no matter be individually dosed or with other active component combination medicine-feeding.Such effect can be objectively (can be measured by some test or label) or subjective (being the indication that the patient provides sensation or effect).
We described " pharmaceutical composition " comprises and is applicable to direct administration mammal, especially Ren Lei compositions.At this on the one hand, this term refers to comprise the preparation that only contains component, and described component is that this area is thought and is suitable for the administration mammal, especially human, patient.In content of the present invention, this term also can refer to the present composition that exists with the liquid form that directly uses at once from the medicine frame, rather than refer to that wherein drug encapsulation need discharge in the water carrier in liposome to avoid medicine in above-mentioned preparation at the intravital preparation of lipid in reconstruct before administration.
We described " homogenizing " refers to that not only the liposome that is included in the present composition is evenly dispersed in the aqueous carrier, refers to further that also active component is distributed in the whole compositions fully.In other words, comprise that medicine in liposome and the aqueous medium, the following formation that is un-encapsulated in the mixture of the medicine in the liposome be unable to do without the formation of following liposome.In some compositions of the present invention, this can produce active component substantially similar concentration in relevant aqueous medium, and no matter described medium is inside or the outside at liposome structure.We described " substantially similar " refers to that described concentration can change approximately ± 50% under room temperature and atmospheric pressure, and be for example about ± 40%, preferred approximately ± 30%, more preferably from about ± 20%, especially is approximately ± 10% (when the inside and outside concentration of liposome structure relatively).Can be for example by standard technique well known by persons skilled in the art
31P-NMR measures drug level and distributes.For example, can use the in-situ investigation technology of standard, or from free water carrier, separate the liposome component and measure the technology of the medicament contg/concentration relevant with every kind of composition.Described separation can realize by centrifugalize, dialysis, ultrafiltration or gel filtration.
Preferably, the present composition also comprises, and pH can be provided is about 4 (for example 4.0) to about pH8 (for example 8.0), and preferably about pH5 (for example 5.0) is the pharmaceutically acceptable buffer of about pH7 (for example 7.0) extremely.Suitable buffer comprises those that can not influence liposome formation, as phosphate (for example sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate or phosphoric acid add alkali salt (phosphoric acid plus base)), citrate (for example sodium citrate or citric acid add alkali salt) or acetate buffer (for example sodium acetate or acetic acid add alkali salt), it can keep pH in above-mentioned specified scope.The use amount of buffer is for being suitable for providing the amount of above-mentioned effect, and this amount is that those skilled in the art are intelligible, and does not need to pay creative work.Suitable consumption is the about 30mg/mL extremely of about 1mg/mL for example.
Those skilled in the art are to be understood that; term " inflammatory diseases " comprises with the part or the general protective reaction that can be caused by physical trauma, infection, those chronic diseases as mentioned above, and/or the chemistry and/or the physiological reaction (for example part of anaphylactic reaction) of stimulus object are any disease of feature to external world.Can be used for destroying, weaken or isolate harmful factor and wounded tissue any this type of reaction can by for example generate heat, swell, bitterly, red, vasodilation and/or blood flow increases, invasion and attack, afunction and/or any other known symptom relevant with inflammatory diseases of leukocyte influence area show.
Therefore, also this term is interpreted as and comprises any inflammatory diseases, disorder and disease of being essentially, any disease with associated inflammatory component, and/or with any disease of inflammatory diseases as symptom, especially comprise acute, chronic, ulcerative, special, hypersensitive and downright bad inflammatory diseases, and other inflammatory diseases form well known by persons skilled in the art.Therefore, be purpose of the present invention, this term also comprises inflammatory pain, common pain and/or fever.
Therefore, the present composition can be used for treating asthma, chronic obstruction pneumonopathy, pulmonary fibrosis, inflammatory bowel, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, lumbago, fibromyalgia, the muscular fasciae disease, viral infection (for example, influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infection, fungal infection, dysmenorrhea, burn, surgery or dental operation, malignant tumor (for example, breast carcinoma, colon cancer, and carcinoma of prostate), high prostaglandin E syndrome, classical Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, fever, ankylosing spondylitis, He Jiejin (family name) disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, apoplexy, diabetes, neurodegenerative disease such as alzheimer's disease and multiple sclerosis, autoimmune disease, anaphylactic disease, rhinitis, ulcer, coronary heart disease, sarcoidosis and any other disease with inflammatory component.
Find that the present composition is specially adapted to treat rhinitis, migraine, acute pain, chronic pain and asthma.Term " rhinitis " will be interpreted as any stimulation and/or the inflammatory diseases that comprises nose, and anaphylaxis or nonallergic comprise that the seasonal rhinitis (for example, is caused by the outdoor factor such as pollen; Pollinosis) and/or perennial rhinitis (for example, causing) and symptom thereof by house dust mite, indoor mycete etc.
The technical staff is to be understood that term " antiinflammatory and/or anti-histamine activity composition " comprises any material, natural product or synthetic product with suitable antiinflammatory and/or antihistamine characteristic.The antiinflammatory compounds comprises steroidal anti-inflammatory medicine (corticosteroid) and nonsteroidal anti-inflammatory drug (NSAIDs), and back one term comprises COX inhibitor, PDE4 inhibitor and leukotriene trim (for example, 5-lipoxidase inhibitor, FLAP inhibitor, LTA
4Hydrolase inhibitor, LTB
4And antihistaminic comprises H receptor antagonist and CysLT (being CysLT1 and CysLT2) receptor antagonist),
1Receptor antagonist.In the context of the present invention, term " antiinflammatory and/or anti-histamine activity composition " also comprises anti-migraine compounds, opioid and analog thereof.
Preferred active component in the present composition comprises anti-histamine activity composition, corticosteroid and leukotriene trim.
The anti-migraine compounds that can mention comprises Almogran, alpiropride, dihydroergotamine, eletriptan, Ergotamine, feverfew (feverfew), frovatriptan, iprazochrome, methysergide, naratriptan, pizotifen, rizatriptan, sumatriptan, Zomitriptan and customary salt thereof.
Opioid and the analog thereof that can mention comprise alfentanil, anileridine, bezitramide; buprenorphine; butorphanol; carfentanil; codeine; dextromoramide; dextropropoxyphene; dezocine; diamorphine; dihydrocodeine; dipipanone; embutramide; ethoheptazine; ethylmorphine; etorphine; fentanyl; hydrocodone; hydromorphone; ketobemidone; levacetylmethadol; levomethadone; levophanol; lofexidine; meptazinol; methadone; morphine; nalbuphine; naltrexone; nicomorphine; opium; oxycodone; oxymorphone; papaveretum; pentazocine; Pethidine; phenazocine; phenoperidine; pholcodine; pirinitramide; remifentanil; sufentanil; tilidate; tramadol and customary salt thereof.
The steroidal anti-inflammatory chemical compound that can mention comprises alclometasone, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, deflazacort, dexamethasone, nerisona, fluocinolone acetonide, fluocinolone acetonide, fluocortolone, fluprednidene, flurometholone, fluticasone, halcinonide, hydrocortisone, methylprednisolone, mometasone, prednisolone, rimexolone and triamcinolone and customary salt thereof.Preferred steroidal anti-inflammatory chemical compound comprises budesonide and fluticasone (for example, the latter who exists with salt form is as propionate).
The NSAIDs that can mention (comprising the COX inhibitor) comprises Aceclofenac; Acemetacin; Antifebrin; Alclofenac; Alminoprofen; Aloxiprin; Aminopyrine; Aminopropylone; Ampiroxicam; Amtolmetin Guacil; Amyl salicylate; Aspirin; Apazone; Bendazac; Benoxaprofen; Benzydamine; BAPN; Bornyl salicylate; Bromofenac; Bufexamac; Bumadizone; Butibufen; Carbasalate; Carprofen; Celecoxib; Clofexamide; Clofezone; Clonixin; Dexketoprofen; Diclofenac; Diflunisal; Analgin; Drogelor; Eltenac; Epirizole; Etodolac; Ethenzamide; Salethyl; Etofenamate; Etoricoxib; Felbinac; Fenbufen; Fenoprofen; Fentiazac; Fepradinol; Feprazone; Floctafenine; Flufenamic acid; Flunixin; Flunoxaprofen; Flurbiprofen; Fosfosal; Furprofen; Glafenine; Glucametacin; Spirosal; Brufen; Ibuproxam; Indomethacin; Ketoprofen; Ketorolac; Lysineaspirin; Mefenamic acid; Meloxicam; Methyl buteneisalicylate; Gaultherolin; Nabumetone; Naproxen; Nedocromil; Nifenazone; Niflumic Acid; Aulin; Olsapozine; Oxyphenbutazone; Paracetamol; Parecoxib; Phenacetin; Antipyrine; Phenylbutazone; Picolaminesalicylate; Piketoprofen; Piroxicam; Pranoprofen; Proglumetacin; Propacetamol; Propyphenazone; Proquazone; Ramifenazone; Rofecoxib; Salamidacetic acid; Salicylamide; Salix (salix); Phenyl salicytate; Salsalate; Nasmil; Salicylate; Thiosalicylate; Sulindac; Suprofen; Suxibuzone; Tenidap; Tenoxicam; Tetridamine; Tetrahydrofurfuryl salicylate; Tiaprofenic Acid; Tiaramide; Tinoridine; Tolfenamic Acid; Tolmetin; Trisalicylate; Trolamine salicylate; Ufenamate; Valdecoxib; Vedaprofen and Zaltoprofen and customary salt thereof.
The concrete PDE4 inhibitor that can mention comprises cilomilast, roflumilast, tetomilast, Piclamilast, and
(aa) CP-671305, (+)-2-[4-({ [benzo [1,3] dioxa cyclopentenyl-5-base oxygen base)-pyridine-3-carbonyl]-amino }-methyl)-3-fluoro-phenoxy group]-propanoic acid,
(bb) SCH351591, N-(3,5-two chloro-1-oxygen-4-pyridine radicals)-8-methoxyl group-2-(trifluoromethyl)-5-quinoline amides,
(cc) KF 19514,5-phenyl-3-(3-pyridine radicals) methyl-3H-imidazo (4,5-c) (1,8)-benzodiazine-4 (5H)-ketone,
(dd) AWD 12-281, N-(3,5-dichloropyridine-4-yl)-(1-(4-luorobenzyl)-5-hydroxyl-indol-3-yl) glyoxamides,
(ee) D 22888,1-ethyl-8-methoxyl group-3-methyl-5-propyl imidazole also (1,5-a) pyrido (3,2-e) pyrazine ketone,
(ff) YM976,4-(3-chlorphenyl)-1, the 7-parvoline is [2,3-d] pyrimidines-2 (1H)-ketone also,
(gg) NVP-ABE171,4-(8-benzo [1,2,5] di azoly-5-base [1,7] benzodiazine-6-yl)-benzoic acid,
(hh) CI-1044, N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydrochysene (1,4) diaza is nicotiamide also-(6,7,1-hi) indol-3-yl)),
(ii) SB 207499, c-4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclohexane-carboxylic acid,
(jj) CC-100004, YM-64227, BAY 19-8004 and GRC 3886,
And customary salt.
CysLT1 that can mention and CysLT2 receptor antagonist comprise abulukast, cinalukast, iralukast, montelukast, pobilukast, pranlukast, sulukast, tomelukast, verlukast, zafirlukast,
(I)BAY-u9773
(II)MK571
And customary salt.The preferred Cys LT receptor antagonist that can mention comprises montelukast.
The 5-lipoxidase inhibitor that can mention comprises following chemical compound.
(1) (synonym: A-64077, ABT 077, Zyflo for zileuton
), be recorded in, for example, EP 0 279263, and US 4,873,259, Int.J.Immunopharmacol.14,505 (1992), Br.J.Cancer 74,683 (1996) and Am.J.Resp.Critical Care Med.157, Part 2,1187 (1998).
(2) A-63162 is recorded in, for example, and Anticancer Res.14,1951 (1994).
(3)A-72694.
(4) A-78773 is recorded in, and for example, Curr.Opin.Invest.Drugs 2,69 (1993).
(5) A-79175 (the R-enantiomer of A78773) is recorded in, for example, and Carcinogenesis 19,1393 (1998) and J.Med.Chem.40,1955 (1997).
(6)A-80263。
(7)A-81834。
(8)A-93178
(9) A-121798 is recorded in, for example, and 211th Am.Chem.Soc.Meeting.211: summary.246.24?March?1996。
(10) atreleuton (synonym ABT-761 and A-85761) is recorded in, and for example, Exp.Opin.Therap.Patents 5 127 (1995).
(11) MLN-977 (synonym LPD-977 and CMI-977) is recorded in, for example, and Curt.Opin.Anti-Inflamm.﹠amp; Immunomod.Invest.Drugs 1,468 (1999).This and similar compounds are recorded in US 5,703,093.
(12) CMI-947 is recorded in, for example, and 215th Am.Chem.Soc.Meeting.215: summary.MEDI?004，29?March?1998。This and similar compounds are recorded in US 5,792,776.
(13) CMI-568 is recorded in, for example, and 211th Am.Chem.Soc.Meeting.211: summary.205，24?March?1996。
(14) LDP 392 (synonym CMI 392) is recorded in, for example, and Pharmacol.Res.44,213 (2001).
(15) linetastine (synonym: linazolast, TMK 688, YM 257) is recorded in, for example, and Int.J.Immunopharmacol.22,123 (2000).
(16) lonapalene (synonym: RS 43179) is recorded in, for example, and Pharm.Res.9,1145 (1992).
Lonapalene
(17) LY-221068 is recorded in, for example, and Ann.N.Y.Acad Sci. (Immunosuppressiveand Antiinflammatory Drugs) 696,415 (1993).
(18) LY269415 is recorded in, for example, and Agents and Actions 42,67 (1994).
(19) has histamine H
1The 5-LO inhibitor of receptor antagonist activity is recorded in, for example, and Bioorg.Med.Chem.Lett.14,2265 (2004), for example following chemical compound.
(20)BF-389
(21) BIL 226 and BIL 357 are recorded in, for example, and J.Pharmacol.Exp.Therap.265,483 (1993).
(22) BU 4601A, BU 4601B and BU 4601C are recorded in, and for example, J.Antibiotics 46,705 (1993).
(23) BW 755C is recorded in, for example, and J.Pharm.Exp.Therap.277,17 (1996).
(24) BW-A4C is recorded in, for example, and Eur.J.Biochem.267,3633 (2000).
(25) BWB 70C is recorded in, for example, and Br.J.Pharmacol.108 (Suppl), 186P (1993).
(26)CBS?1108。
(27) CGS 26529, be recorded in, for example, Inflamm.Res.44 (Suppl.2) 147 (1995).
(28) CGS 25667, CGS 25997 and CGS 25998 are recorded in, for example, and J.Med.Chem.38,68 (1995).
(29) CGS-23885 is recorded in, for example, and J.Med.Chem.36,3580 (1993).
(30)CI-986
(31) CT3 (synonym: ajumelic acid, DMH-11C, HU 239) is recorded in, for example, and J.Med.Chem.35,3153 (1992).
(32) CV 6504, be recorded in, for example, Ann.Oncol.11,1165 (2000).
(33) darbufelone (synonym: CI-1004, PD 136095-0073) and analog, be recorded in, for example, Arthritis and Rheumatism 42 (Suppl.) 404 (1999), ibid 42 (Suppl.) 81 (plus poster) (1999) and J.Med.Chem.37,322 (1994).
(34) docebenone (synonym AA861) and analog thereof are recorded in, for example, and Int.Arch.Allergy and Immunol.100,178 (1993) and Biochim.Biophys.Acta 713,470 (1982).
(35) DuP 654, be recorded in, for example, J.Med.Chem.33,360 (1990).
(36) XA 547, be recorded in, for example, BTG International Inc.CompanyCommunication 15 Oct 1999 and Bioorg.Med.Chem.3,1255 (1995).
(37)E-3040
(38) E 6080, be recorded in, for example, Res.Commun.Mol.Pathol.Pharmacol.86,75 (1994).
(39)E?6700.
(40) Epocarbazolin A, a kind of chemical compound of from Streptomyces anulatus T688-8, separating and being recorded in, for example, J.Antibiotics 46,25 (1993).
(41) ER 34122, be recorded in, for example, Inflamm.Res.47,375 (1998).
(42) ETH 615, be recorded in, for example, Exp.Dermatol.2,165 (1993).
(43) F 1322, be recorded in, for example, XV International Congress of Allergology andClinical Immunology (Suppl 2) 325 (1994).
(44) Flezalastine (synonym: D 18024, IDB 18024) is recorded in, for example, and Allergy (Suppl.) 47,47 (1992).
(45) nitrogen Si spit of fland is recorded in, for example, and Int.Arch.Allergy and Applied Immunol.90,285 (1989).
(46) FPL 62064, be recorded in, for example, Agents and Actions 30,432 (1990).
(47) FR 110302, be recorded in, for example, Am.Rev.Resp.Dis.145, A614 (1992).
(48) HP 977 and P 10294 are recorded in, for example, and J.Med.Chem.39,246 (1996).
(49)P-8977
(50) HX-0835 is recorded in, for example, and Rinsho Iyaku.11,1577 ﹠amp; 1587 (1995).
(51) HX-0836 is recorded in, and for example, J.Med.Chem.36 3904 (1993).
(52) following chemical compound is recorded in Bioorg.Med.Chem.Lett.6, and 93 (1996).
(53) Icodulinium (synonym: CBS 113A, icoduline) is recorded in, for example, and Arzneimittel-Forschung (Drug Research) 39,1242 ﹠amp; 1246 (1989).
(54) KC-11404 is recorded in, for example, and Eur.Resp.J.7 (Suppl.18), 48 (1994).
(55)KC-11425
(56)KME?4.
(57) L 651392, be recorded in, for example, Adv.Prostaglandin, Thromboxane andLeukotriene Res.17,554 (1987).
(58)L?651896.
(59)L?652343.
(60)L?653150.
(61) L-656224 is recorded in, for example, and J.Gastroenterol.Hepatol.11,922 (1996).
(62) L-702539 is recorded in, for example, and J.Med.Chem.37,512 (1994).
(63)L-670630.
(64) L-691816 is recorded in, and for example, Curr.Opin.Invest.Drugs 2,683 (1993).
(65) L 699333, be recorded in, for example, J.Med.Chem.38,4538 (1995).
(66)L?739010。
(67) Lagunamycin is recorded in, and for example, J.Antibiotics 46,900 (1993).
(68) Licofelone (synonym: ML 3000) is recorded in, for example, and Eur.J.Pharm.453,131 (2002) and J.Med.Chem.37,1894 (1994).
(69)PD?145246。
(70) R 840 (synonym: S 26431).
(71) R 68151, be recorded in, for example, Arch.Dermatol.128,993 (1992).
(72) R 85355, be recorded in, for example, Skin Pharmacol.9,307 (1996).
(73) REV 5901 (synonym: PF 5901, Revlon 5901, RG 5901) is recorded in, for example, and J.Allergy Clin.Immunol.91,214 (1993).
(74) RWJ 63556, be recorded in, for example, 214th Am.Chem.Soc.Nat.Meeting. summary.MEDI?091(1997)。
(75) S 19812, be recorded in, for example, Mediators of Inflammation 8 (Suppl.1), 134﹠amp; 135 (1999).
(76) SC 45662, be recorded in, for example, J.Allergy and Clin.Immunol.89,208 (1992)
(77)SC-41661A
(78)SCH?40120。
(79)SKF-86002
(80) SKF 104351 and SKF 105809.
(81) SKF-107649 is recorded in, for example, and J.Med.Chem.39,5035 (1996).
(82) T0757 and T0799), be recorded in, for example, Jap.J.Pharmacol.66,363 (1994).
(83) TA 270, be recorded in, for example, Naunyn-Schmiedeberg ' s Arch.Pharmacol.358 (Suppl.2) 737 (1998).
(84) Tagorizine (synonym: AL 3264) is recorded in, for example, and Jap.J.Pharmacol.65,19 (1994) and ibid.64 (Suppl.1), 312 (1994)
(85) tepoxalin (synonym: ORF 20485, RWJ 20485) is recorded in, for example, and J.Pharmacol.Exp.Therap.271,1399 (1994).
(86) UPA 780, be recorded in, for example, Inflamm.Res.44 (Suppl.3), 273 (1995).
(87)VUFB?19363.
(88) VZ 564, be recorded in, for example, Arzneimittel-Forschung (Drug Research) 25,155 (1995).
(89) following chemical compound is recorded in J.Med.Chem.40, and 819 (1997).
(90)WAY?120739.
(91) WAY 121520, be recorded in, for example, Agents and Actions 39 (Spec.issue C1) C30 (1993) and Exp.Opin.Invest.Drugs 6,279 (1997).
(92) WAY-126299A is recorded in, for example, and Inflamm.Res.44 (Suppl.2), 170 (1995).
(93) WAY-125007 is recorded in, and for example, WO 04/004773
(94) WHIP 97, be recorded in, for example, 216th Am.Chem.Soc.Nat.Meeting. summary.MEDI?363(1998)。
(95) WY 28342, be recorded in, for example, J.Med.Chem.38,1473 (1995).
(96) WY 50295 (the S-enantiomer of WY 49232) is recorded in, for example, and Eur.J.Pharmacol.236,217 (1993).
(97) ZD 2138 (synonym: ICI D 2138), be recorded in, for example, Asthma 95:Theoryto Treatment 15 (1995) and Trends in Pharm.Sci.13,323 (1992).
(98) ZM 230487 (synonym: ICI 230487) is recorded in, and for example, Inpharma 660,9 (1994).
(99) ZD 4007 and ZD 4407 are recorded in, and for example, EP 0 623 614.
(100) ZD 7717, are recorded in, and for example, EP 0 462 813.
(101)ZM-216800
(102) CJ-12,918 and analog, be recorded in, for example, Bioorg.Med.Chem.11,3879 (2003).
(103), be described as the chemical compound of blended 5-LO/COX-2 inhibitor in 779 (2002), as following chemical compound at Bioorg.Med.Chem.Lett.12.
(104) AKBA (acetyl group-11-ketone-β-boswellic acid) is recorded in, for example, and Br.J.Pharmacol.117,615 (1996) and Eur.J.Biochem.256,364 (1998).
(105) at Eur.J.Med.Chem.22; 147 (1997) and Arzneimittel-Forschung (DrugResearch) 35; be described as the chemical compound of dual 5-LO and COX inhibitor in 1260 (1985), for example 2-acetyl thiophene-2-thiazolyl hydrazone (CBS-1108) and N-phenyl benzamidrazone.
(106) Olibanum (from the extract of Boswellia serrata acquisition) is recorded in, for example, and FifthChemical Congress of North America, Abstract 01/1351 (1997) and ibid.Abstract01/1350 (1997).
(107) 2, for example, US 5,985, are described as the 5-LO inhibitor in 937.
(108) nicaraven is recorded in, and for example, Curr.Opin.Invest.Drugs 4,83 (2003).
Nicaraven
(109) tenidap is recorded in, and for example, EP 0 156 603, and US 4,556,672, ArthritisRheum.31, Suppl.S52 (1988) and P.Katz et al., ibid.S52.
(110) at J.Med.Chem.39,3938 (1996), in be described as ring-type hydrazides such as phenidone, 1-phenyl-2H-tetrahydro pyridazine-3-ketone and the 1-phenyl perhydro-1,2 of 5-LO inhibitor, 4-tetrahydrochysene pyrazine-3-ketone,
Phenidone
(111) ICI 207968, be recorded in, for example, J.Med.Chem.34,1028 (1991).
(112) ICI 211965 and other (methoxyl group alkyl) thiazole are recorded in, for example, and J.Med.Chem.34,2176 (1991).
(113) be recorded in J.Med.Chem.32,1006 (1989) 2,3-dihydro-5-benzofuran alcohol is as following chemical compound.
(114) be recorded in Bioorg.Med.Chem.11,2 in 4207 (2003), 6-two-tert-butyl benzene amphyl is as tebufelone, R-830 and S2474.
Tebufelone
(115) at J.Med.Chem.41, be described as the 7-tert-butyl group-2 of 5-LO/COX-2 inhibitor in 1112 (1998), 3-dihydro-3, the 3-dimethyl benzofuran is as PGV-20229.
(116), be described as the chemical compound of dual 5-LO/COX inhibitor in 1897 (2003), as following chemical compound at Eur.J.Med.Chem.35.
(117) autumnolide, a kind of Sesquiterpene obtain that separates from several plant speciess of Asteraceae section is recorded in, Biochem.Pharm.62 for example, 903 (2001).
(118) AS-35, (9-[(4-acetyl group-3-hydroxyl-2-n-pro-pyl phenoxy group) methyl]-3-(1H-tetrazolium-5-yl)-4H-pyrido [1,2-a] pyrimidin-4-one), be recorded in, for example, Int.J.Immunopharmacol.22,483 (2000).
(119) Magnolol is recorded in, and for example, Planta Medica 65,222 (1999).
(120) honokiol, extraction obtains from Chinese herbal medicine, and is recorded in, for example, Arch.Allergyand Immunol.110,278 (1996).
(121) chrysarobin.
Chrysarobin
(122)E-3040。
(123) Flobufen is recorded in, and for example, Chirality 16,1 (2004).
(124) YPE-01 is recorded in, for example, and Eur.J.Pharmacol.404,375 (2000).
(125)BW-A137C
(126)LY-233569
(127)PD-138387
(128)SB-210661
(129)DuP-983
(130)BTS-71321
(131) Piripost is recorded in, for example, and Toxicon.24,614 (1986).
(132) MK-866 is recorded in, for example, and Eur J Pharmacol 205,259 (1991).
(133) UCB 62045, are recorded in, and for example, Chest 123,371S (2003).
(134) ONO-LP-049 is recorded in, for example, and J.Immunol.140,2361 (1988).
(135) 3323W, L-697198, L-7080780, FR-122788, CMI-206, FPL-64170 and PD-089244
And customary salt.Preferred 5-lipoxidase inhibitor comprise zileuton or, nitrogen Si spit of fland more specifically.
The specific 5-LO inhibitor of other that can mention comprises that those are recorded in comment Prog.Med.Chem., G.P.Ellis and D.K.Luscombe, Elsevier 29,1 (1992) and J.Med.Chem.14, the chemical compound in 2501 (1992).
The special FLAP inhibitor that can mention comprises following chemical compound.
(a) L-674,573 and relevant FLAP inhibitor (for example L-655,238), be recorded in, for example, Mol.Pharmacol.40,22 (1991).
(b) L-674,636, be recorded in, for example, J.Med.Chem.38,4538 (1995).
(c) L-689,037 and the affine analog of light [
125I]-669,083 and [
125I]-691,678, be recorded in, for example, Mol.Pharmacol.41,267 (1992).
(d) L-705,302, be recorded in, for example, J.Med.Chem.38,4538 (1995).
(e) MK-886 (synonym: L663536, MK 0886) is recorded in, for example, US 5,081,138, Am.Rev.Resp.Dis.147,839 (1993), Eur.J.Pharmacol.267,275 (1994), TheSearch for Anti-Inflammatory Drug.233 (1995) Eds.:V.J.Merluzzi and J.Adams, Boston, Birkh user.
(f) be similar to the chemical compound of MK-886 on the structure, be recorded in, for example, WO 93/16069, US5,308,850 and WO 94/13293.
(g) quiflapon (synonym: MK-591, L 686708) is recorded in, for example, and J.Physiol.Pharmacol.70,799 (1992) and J.Lipid Mediators 6,239 (1993).
(h) BAY X 1005, are recorded in, and for example, Thorax 52,342 (1997).
(i) BAY Y 105, be recorded in, for example, Arthritis and Rheumatism 39,515 (1996) and Drug ﹠amp; Market Devel.7,177 (1996).
(j) VML 530 (synonym: ABT 080) is recorded in, and for example, Pharmacologist 39,33 (1997)
And customary salt.
The LTA that can mention
4Hydrolase inhibitor comprises following chemical compound.
(A) at US 5,455,271 and WO 94/00420 in be described as LTA
4The chemical compound of hydrolase inhibitor, for example:
(B), be described as LTA in 211 (1993) and J.Am.Chem.Soc.114,6552 (1992) at J.Med.Chem.36
4The chemical compound of hydrolase inhibitor is as following chemical compound.
(C) chemical compound that can utilize the method for the claim 24 of WO 00/50577 to confirm.
(D), be described as LTA in 876 at US 6,506
4The chemical compound of hydrolase inhibitor is as SC-56938.
(E) analog of SC-56938 is recorded in, for example, and Bioorg.Med.Chem.Lett.12,3383 (2002).
(F), be described as LTA in 306 at US 5,719
4The chemical compound of hydrolase inhibitor, for example:
(G) in WO 96/11192, be described as LTA
4The chemical compound of hydrolase inhibitor, for example:
(H) at US 6,265,433 and WO 98/40364 in be described as LTA
4The chemical compound of hydrolase inhibitor, for example:
(I) at US 6,506,876 and WO 96/10999 in be described as LTA
4The chemical compound of hydrolase inhibitor, for example:
And
(J) in WO 98/40370, be described as LTA
4The chemical compound of hydrolase inhibitor, for example:
(K) in WO 98/40354, be described as LTA
4The chemical compound of hydrolase inhibitor,
(L) in EP 0 360 246, be described as LTA
4The chemical compound of hydrolase inhibitor (3-oxirane yl benzoic acid), for example:
(M) 20,20,20-trifluoro leukotriene B4 derivant is recorded in, and for example, JP 01211549 A2 is as following chemical compound.
(N) in EP 1 165 491 and WO 00/059864, be described as LTA
4The chemical compound of hydrolase inhibitor, as 2-amino-6-(4-benzyl phenoxy group) caproic acid:
(O) at US 6,436,973 and WO 00/017133 in be described as LTA
4The chemical compound of hydrolase inhibitor, as (2S, 3R)-2-amino-3-(benzyloxy) butane-1-mercaptan:
(P), be described as LTA in 969 (1995) at Bioorg.Med.Chem.3
4The chemical compound of hydrolase inhibitor, for example:
(Q) in DE 4121849 A1, be described as LTA
4[4-(ω-aryl alkyl) phenyl] chain acid compound of hydrolase inhibitor, for example:
(R) in DE 4118173 A1, be described as LTA
4The chemical compound aralkyl thienyl alkanoate of hydrolase inhibitor, for example:
(S) in DE 4118014 A1, be described as LTA
4The ω of hydrolase inhibitor-[(4-aralkyl) thiophene-2-y1] alkanoate, for example:
(T), be described as LTA in 3156 (1992) at J.Med.Chem.35
4Hydrolase inhibitor, as RP64966:
(U) be similar to the chemical compound of RP66153 and be recorded in J.Med.Chem.35,3170 (1992) on the structure.
(V) in DE 4314966 A1, be described as LTA
4The different azoles of the 2-hydroxy phenyl-replacement of hydrolase inhibitor, for example:
(W) bestatin is recorded in, and for example, J.Nat.Cancer Institute 95,1053 (2003).
(X) SC-22716 (1-[2-(4-phenyl phenoxy group) ethyl] pyrrolidine) is recorded in, for example, and J.Med.Chem.43,721 (2000).
(Y) SC57461A is recorded in, for example, and J.Med.Chem.45,3482 (2002) and Curr.Pharm.Design 7,163 (2001).
(Z), be described as LTA in 1137 (2003) at Bioorg.Med.Chem.Lett.13
4The imidazopyridine of hydrolase inhibitor and purine.
(AA) captopril is recorded in, and for example, FASEB Journal 16,1648 (2002).
(AB) in WO 99/40910, be described as LTA
4The hydroxamic acid derivs of hydrolase inhibitor, for example:
(AC) AB5366 is recorded in, for example, and JP 11049675 A2.
(AD) SA6541 is recorded in, and for example, WO 96/27585, Life Sci.64, PL51-PL56 (1998) and Eur.J.Pharmacol.346,81 (1998).
(AE) in JP 10265456 A2, be described as LTA
4The chemical compound that comprises N-sulfydryl acyl group proline of hydrolase inhibitor, for example:
(AF) amphotericin B is recorded in, for example, and Prostaglandins, Leukotrienes andEssential Fatty Acids 58,105 (1998).
(AG) 14,15-dehydrogenation leukotriene A is recorded in, for example, and Biochem.J.328,225 (1997).
(AH) 8 (S)-amino-2 (R)-methyl-7-oxo n-nonanoic acid is produced and is recorded in by Streptomyces diastaticus, and for example, J.Natural Products 59,962 (1996).
(AI) comprise the peptide kelatorphan of hydroxamic acid, be recorded in, for example, Bioorg.Med.Chem.Lett.5,2517 (1995).
(AJ), be described as LTA in 1405 (1995) at Bioorg.Med.Chem.3
4The amino hydroximic acid of hydrolase inhibitor, for example:
(AK), be described as LTA in 31 (1995) at J.Pharmacol.Exp.Therap.275
4α-the ketone group of hydrolase inhibitor-beta-amino ester and sulfo-amine.
(AL) in JP 05310668 A2, be described as LTA
4The N-of hydrolase inhibitor (phenyl bytyry) leucine
And customary salt.
The special LTA of other that can mention
4Hydrolase inhibitor comprises and is recorded in comment Curr.Pharm.Design 7,163 (2001) and Curr.Med.Chem.4, those in 67 (1997).
The LTB that can mention
4Receptor (for example BLT1) antagonist comprises following chemical compound.
(i), be described as LTB in 530 at US 6,291
4The chemical compound of receptor antagonist, as (E)-[5-(2-diethylamino formoxyl-1-methyl ethylene)-2-(2,6-two fluoro-benzyloxies) phenoxy group] acetic acid:
(ii) in US 2002/0128315, be described as LTB
4The chemical compound of receptor antagonist, as 4-(4-Phenylpiperidine ylmethyl) benzoic acid 4-amidino groups phenylester and 4-(2-phenylimidazole ylmethyl) benzoic acid 4-amidino groups phenylester:
(iii) in US 2004/0053962, be described as LTB
4The chemical compound of receptor antagonist, as 2-(2-propyl group-3-(3-(2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy) propoxyl group) phenoxy group) benzoic acid:
(iv) BIIL is recorded in, for example, and J.Pharmacol.Exp.Therap.297,458 (2001) and WO 02/055065.
(v) CP 105696 and CP 195543 are recorded in, for example, and J.Pharmacol.Exp.Therap.285,946 (1998).
(vi)LY?210073
(vii) LY 223982 (synonym: CGS 23131, SKF 107324).
(viii) LY 255283 (synonym: CGS 23356, LY 177455) is recorded in, for example, and Eur.J.Pharmacol.223,57 (1992).
(ix)LY?292728。
(x) LY 293111 (synonym: VML 295) is recorded in, for example, and Drugs of the Future 21,610 (1996), Clin.Cancer Res.8,3232 (2002) and WO 01/085166.
(xi)LTB?019.
(xii) (synonym: CGS 25019C), be recorded in, for example, Exp.Opin.Therap.Patents 5,127 (1995) for moxilubant.
Moxilubant
(xiii) (KW 4679, Patanol for synonym: allelock, ALO 4943A for Olopatidine
), be recorded in, for example, Drugs of the Future 18,794 (1993).
(xiv) ONO 4057 (synonym: LB 457) is recorded in, for example, and Gastroenterology 110 (Suppl.), 110 (1996).
(xv) ontazolast (synonym: BIRM 270) is recorded in, for example, and J.Pharm.Exp.Therap.271,1418 (1994).
(xvi) PF 10042, be recorded in, for example, Eur.J.Pharmacol.-EnviromentalToxicology and Pharmacology Section 293,369 (1995).
(xvii) RG 14893, are recorded in, and for example, Pharmacologist 34,205 (1992).
(xviii) RO 254094, are recorded in, and for example, ISSX Proceedings 6,232 (1994).
(xix)RP?66153。
(xx)RP?66364。
(xxi)RP?69698.
(xxii) SB 201146, are recorded in, and for example, Thorax 53,137 (1998).
(xxiii) SB 201993, be recorded in, for example, J.Med.Chem.36,2703 (1993).
(xxiv) SC 41930, be recorded in, for example, J.Pharmacol.Exp.Therap.269,917 (1994).
(xxv)SC?50605。
(xxvi)SC?51146。
(xxvii) SC 53228, be recorded in, for example, Inflammation Res.44 (Suppl.2), 143 (1995).
(xxviii) ticolubant (synonym: SB 209247) is recorded in, for example, and Adv.ProstaglandinThromboxane and Leukotriene Res.23,275 (1995).
(xxix) U 75302 (synonym: U 75485, U 77692, U 78489) is recorded in, for example, and Adv.Prostaglandin Thromboxane and Leukotriene Res.23,275 (1995).
(xxx) VM 301 (synonym: OAS 1000, pseudopterosin A methyl ether) is recorded in, for example, and Inflammation Res.44, (Suppl.3) 268 (1995).
(xxxi) ZD 158252, are recorded in, and for example, Inpharma 1094,9 (1997).
(xxxii) ZK 158252, are recorded in, and for example, Inpharma 1094,9 (1997).
(xxxiii) U-75509 is recorded in, for example, and Am.J.Physiol.Heart Circ.Physiol.2004, Mar 11[Epub ahead of print].
(xxxiv) CP-105,696, be recorded in, for example, Br.J.Pharmacol.139,388 (2003).
(xxxv) LY293111 is recorded in, for example, and Clin.Cancer Res.8,3232 (2002) and customary salt.
The H that can mention
1Histamine receptor antagonists comprises acrivastine, alimemazine, anatazoline, astemizole, azatadine, nitrogen Si spit of fland, bamipine, bepotastine, bromazine, bromopheniramine, buclizine, carbinoxamine, chloreyclizine, chloropyramine, chlorophenamine, cinnarizine, clemastine, clemizole, clocinizine, cyclizine, Cyproheptadine, deptropine, Desloratadine, dexchlorpheniramine, dimenhydrinate, dimetindene, dimetotiazine, diphenhydramine, piphenylpyraline, doxylamine, ebastine, embramine, emedastine, epinastine, fexofenadine, flunarizine, homochlorocyclizine, hydroxyzine, isothipendyl, levocarbastine, loratidine, mebhydroline, meclizine, pyrilamine, mequitazine, methdilazine, mizolastine, niaprazine, olopatadine, oxatomide, oxomemazine, phenindamine, pheniramine, phenyltoloxamine, pimethixene, pipinhydrinate, promethazine, propiomazine, quifenadine, ruputadine, setastine, Compound Terfenadine Tablete, thenyldiamine, thiethylperazine, the thonzylamine, tolpropamine, trimethobenzamine, tripelennamine, triprolidine and tritoqualine and customary salt thereof.
Active component can be united use.
Any officinal salt and the free alkali form thereof of antiinflammatory and/or anti-histamine activity composition can be used to make the present composition.Preferred salt comprises acetate, pyruvate, aluminum salt, ammonium salt, arginine salt, bromine salt, butyrate, calcium salt, villaumite, choline salt, citrate, diethanolamine salt, the diethyl amine salt, dipropionate, embonate, ethanolamine salt, ethylenediamine salt, formates, fumaric acid, fuoratesalts, hydrobromate, hydrochlorate, imidazole salts, lactate, lysinate, magnesium salt, malate, maleate, malonate, meglumine salt, mesylate, alkylbenzyldimethylasaltsum saltsum, nitrate, phosphate, piperazine salt, potassium salt, propionate, sodium salt, succinate, sulfate, tartrate, teoclate, tosilate, triethanolamine salt, triethylamine salt, valerate etc. and/or as " Handbook of Pharmaceutical Salts ", Eds.Stahl and Wermuth, Wiley, 2002, the salt described in the Chapter 12.
Can be used for preparing the antiinflammatory of the present composition and/or the amount of anti-histamine activity composition or its salt can be determined according to the amount that is suitable for most individual patient by doctor or technical staff.It can change according to the order of severity and subject concrete species of patient, age, body weight, sex, renal function, liver function and the reaction of the character of used active component, subject disease.Yet preferably, the present composition comprises that calculating content with free alkali form is antiinflammatory and/or hydryllin or its salt of about 0.1mg/mL to about 200mg/mL.
The total amount that active component can exist can be enough to provide dosage every day of the unit dose drug that is suitable for using active component.For example, described every day, dosage can be about 20 μ g to about 200mg.Those of ordinary skill in the art is to be understood that the present composition can one or more administering modes, be administered once every day or repeatedly provide aforesaid every day dosage.Preferred range comprises that about 0.1mg/mL is to about 100 (for example, about 70) mg/mL and more preferably about 0.2mg/mL to 50mg/mL.
Above-mentioned dosage is the example of general dosage form; Certainly, can exist have higher or than the low dosage scope the example, these dosage are all within the scope of the invention.
Term " liposome " comprises the structure of being made up of one or more homocentric spheres of polar lipid bilayer for those skilled in the art can understand, and described bilayer is separated by water or aqueous buffer solution compartment.
Liposome can be prepared by several different methods, uses solvent, decompression, binary system, lyophilization, supersound process etc., for example at Liposome Drug Delivery Systems, and people such as Betageri G V.Technomic Publishing AG, Basel, Switzerland describes in 1993, and disclosed related content is incorporated herein by reference in the document.
Term " polar lipid " is that the technical staff is understandable, comprises any lipid of have polar head group (polarhead-group) and two fatty acid residues, and it can form liposome.
Polar lipid, for example described below those, can be natural and/or synthetic/semi-synthetic source.In the present composition, also can use natural and mixture synthetic/semisynthetic polar lipid.
Therefore, the polar lipid that uses in the present composition can be based on for example phospholipid, especially phosphatidylcholine (PC), phosphatidyl glycerol (PG), phosphatidylinositols (PI), phosphatidic acid (PA), Phosphatidylserine (PS) or its mixture.
The phospholipid that uses in the present composition comprises polarity or non-polar group, and it is connected to the main chain entity for example on the glycerol that is loaded with hydroxyl.
Phospholipid also can be represented by general formula I
R wherein
1And R
2Expression has the branched-chain or straight-chain alkyl of saturated or unsaturated (for example alkenyl) of 7 to 23 carbon atoms, preferred 11 to 19 carbon atoms independently; R
3Represent amide or ester in conjunction with base, as
-CH
2-CH (OH)-CH
2OH (phosphatidyl glycerol),
-CH
2-CH
2-N (CH
3)
3(phosphatidylcholine),
-CH
2-CH
2-NH
2(PHOSPHATIDYL ETHANOLAMINE),
-H (phosphatidic acid), or
-CH
2-CH (NH
2)-COOH (Phosphatidylserine).
Described phospholipid can be natural origin.The phospholipid of natural origin preferably derives from the plant source (for example Semen Brassicae campestris, Helianthi etc., or, preferred Semen sojae atricolor) of separate sources and the membrane lipid of animal sources (for example egg yolk, milk etc.).From the phospholipid of Semen sojae atricolor, main plant phospholipid source, the common by-product (being lecithin) that gets in the thick Oleum Glycines of free method for degumming refine.Lecithin can further use other physical location operation (physical unit operations) to handle and purification, for example fractionating process and/or chromatography.Other phospholipid also can then by solvent extraction, then handle obtaining as stated above by multiple suitable seed of extruding and grain.The phospholipid of the natural origin that can mention for example comprises that (it all is the mixture of several different phospholipid of finding for Lipoid GmbH, Germany) those of Chu Shouing with trade name Lipoid S75, Lipoid S100 and Lipoid S75-3N in Semen sojae atricolor.
Described phospholipid can be synthetic or semi-synthetic source (that is, by the chemosynthesis preparation).For example, can adopt the multistep chemical synthesis process, obtaining main phospholipid intermediate 1, the 2-DG, from (S)-1, the 2-acetone glycerol, it is the glycerol backbone of feature that the latter provides with phospholipid.When corresponding polar head group is connected to 1 via chemosynthesis, 2-DG intermediate then can obtain 1, the phospholipid of 2-diacetylation.Yet the source of glycerol that uses in a plurality of steps and fatty acid can be natural origin and synthetic source usually.Synthetic and/or the semisynthetic phospholipid that can mention comprises dilauryl phosphatidylcholine (dilaurylphosphatidylcholine; DLPC); myristyl phosphatidylcholine (dimyristolphosphatidylcholine; DMPC); two palmityl phosphatidylcholine (dipalmitoylphosphatidylcholine; DPPC); two Laurel acyl phospholipids acyl glycerol (dilaurylphosphatidylglycerol; DLPG); myristyl phosphatidyl glycerol (dimyristolphosphatidylglycerol; DMPG); dioleyl phosphatidyl choline (dioleoylphosphatidylcholine; DOPC) and the dioleoyl phosphatidyl glycerol (dioleoylphosphatidylglycerol, DOPG).
Polar lipid also can comprise glycolipid (glycolipid), or more preferably is made up of glycolipid.In content of the present invention, term " glycolipid " refers to comprise the chemical compound of one or more monosaccharide residues, and described residue is bonded to hydrophobic parts by glycosidic bond, for example acylglycerol, sphingol or ceramide (N-acyl group sphingolipid).
Glycolipid can be glycosyl glyceride matter (glycoglycerolipid).In content of the present invention, term " glycosyl glyceride matter " refers to comprise the glycolipid of one or more glycerol residue.The preferred aspect according to the present invention, glycosyl glyceride matter comprise the galactose glyceride or be made up of the galactose glyceride, the digalactosyl DG of general formula I I more preferably,
R wherein
1And R
2For defined above.
Described glycolipid also can be a glycosyl sphingolipid (glycosphingolipid).In the context of the present invention, term " glycosyl sphingolipid " refers to comprise the lipid of at least one monosaccharide residue and sphingol or ceramide.Therefore, this term can comprise neutral glycosyl sphingolipid, as single and oligomeric glycosyl sphingolipid and oligomeric and preferred monoglycosylceramide.This term also can comprise acid glycosyl sphingolipid, as sialoglycosphingolipids, uronoglycosphingolipids, sulfo group glycosyl sphingolipid, phosphoric acid glycosyl sphingolipid and phosphono glycosyl sphingolipid.Described glycosyl sphingolipid can be ceramide, single hexose ceramide, two hexose ceramides, sphingomyelins, lysosphingomyelin, sphingol or its mixture.Preferably, glycosyl sphingolipid is sphingomyelins or its derivative products.Described sphingomyelin content is preferably by chromatography to be determined.Sphingomyelins can extract from milk, preferred milk, brain, egg yolk or from the erythrocyte of animal blood, the preferred sheep of described animal.For fear of doubt, synthetic and semisynthetic sphingolipid is also included among the present invention.
Alternatively, glycolipid can be a glycophosphatidyl inositol.In the context of the present invention, term " glycophosphatidyl inositol " refers to comprise the glycolipid that the glycosidic bond of sugar is connected to the inositol part of phosphatidylinositols.
Preferred glycolipid comprises digalactosyl DG (DGDG).
Preferably, polar lipid based on phospholipid and more preferably derive from Semen sojae atricolor phospholipid (for example, Lipoid S100, Lipoid S75 or Lipoid S75-3N).
Preferred polar lipid (for example phospholipid) for those in water solvable be expanded into the degree that can measure those and/or can spontaneously form those of liposome.
If polarity (for example phosphorus-) fat can not be in water swelling spontaneously, those of ordinary skill in the art then can recognize and add for example anion (for example phosphorus-) fat (for example phosphatidyl glycerol) of (for example phosphorus-) high polarity more, swellable fat, still might obtain liposome.
If (chain dissolves acyl chain; Gel is to liquid crystalization) phase transition temperature be lower than the freezing point of water, liposome forms and can carry out being higher than under about 0 ℃ (for example room temperature).
No matter use any polar lipid material (or its combination), the suitable total amount/concentration of spendable lipid is that about 10mg/mL is to about 120mg/mL in the preparation of the present composition.The present composition that can mention comprise following those: when polar lipid comprise phospholipid (no matter be with another kind of lipid or with other combination) time, the amount of phospholipid is about 10 (for example about 17 in the compositions, for example about 20) mg/mL is to about 120mg/mL, more preferably about 25 (for example about 35) mg/mL is to about 100 (for example about 70, for example about 50, for example about 40) mg/mL.The typical range that can mention comprises that about 25 (for example, 27) mg/mL is to about 50mg/mL (for example 45 or more preferably 35mg/mL).In addition, phospholipid total amount (when polar lipid comprises phospholipid) is preferably about 10mg to about 80mg (according to appointment 17 (for example 20) mg extremely about 70 (for example 40) mg).
The present composition also can comprise antioxidant, as alpha-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaric acid, malic acid, monothioglycerol, propanoic acid, propyl gallate, sodium ascorbate, sodium sulfite, sodium pyrosulfite, potassium metabisulfite, sodium sulfite, tartaric acid or vitamin E.Preferred anti-oxidants comprises butylated hydroxytoluene, alpha-tocopherol, ascorbic acid and butylated hydroxyanisole.
According to the present invention, can use chelating agen to reduce the metal ion of catalytic oxidation phospholipid and/or active component.The example of useful chelating agents is ethylenediaminetetraacetic acid (EDTA) and salt (for example, EDTA sodium salt or potassium salt), ethylenediamine triacetic acid and diethylene-triamine pentaacetic acid (DTPA).Also can use other reagent to protect the present composition, especially, any undersaturated fatty acid that herein can exist can be prevented oxidation.Preferred chelating agen comprises EDTA and salt thereof.
The present composition can comprise one or more antiseptic.The example that is generally used for the antiseptic of composition of liquid medicine is Benasept, benzoic acid, butylated hydroxyanisole, butoben, methaform, ethyl hydroxybenzoate, methyl hydroxybenzoate, propylparaben, phenoxyethanol or phenethanol.Preferred antiseptic comprises Benasept.Other antiseptic can be mentioned comprises sorbic acid.
In order to make the present composition be retained in its application site, its also can comprise viscosifier as, for example hydrophilic polymer such as Polyethylene Glycol or crosslinked polyvinylpyrrolidone and/or cellulose derivative such as hydroxypropyl methylcellulose.Viscosifier also can play protective colloid, in fact to stablize the present composition before administration.Preferred protective colloid comprises hydroxypropyl methylcellulose and more preferably Polyethylene Glycol.
The present composition also can comprise flavoring agent (for example Fructus Citri Limoniae, Mentholum or lavender powder) and/or sweeting agent (for example neohesperidin).
The present composition also can comprise tension regulator, as sodium chloride, potassium chloride, glycerol, glucose, dextrose, sucrose, mannitol etc.
Optional additive comprises buffer, antiseptic, viscosifier, antioxidant, tension regulator and chelating agen, all can select according to their characteristic and use amount, should guarantee that they should be retained to minimum to harmful effect of liposome stability.For given reagent, can understand by the technical staff and simply test in the scope to determine.Yet the Sq of these compositions is that about 0.01mg/mL is to about 10mg/mL.Preferably, the present composition comprises at least a antiseptic, antioxidant, chelating agen, buffer and/or viscosifier.The Sq of any/all these optional additives comprises about 0.02 to about 5 (for example, about 3) mg/mL (for example, about 0.1 to about 2mg/mL).
The method for preparing the present composition also is provided.We be surprisingly found out that can by with the direct swelling of polar lipid in aqueous medium, and do not need to add any other for example charged lipid of common needs and/or the excipient of surfactant etc. prepare liposome.
According to a further aspect in the invention, provide the method for preparing the present composition, this method comprises:
(a) with (i) polar lipid or mixture, it is swellable in aqueous medium, and (ii) water is with (iii) antiinflammatory and/or anti-histamine activity composition mix; And
(b) preparation that homogenizes.
The water that uses in the above-mentioned steps (a) comprises water, or wherein is dissolved with the water (being aqueous solution) of other material.Aqueous solution for example can comprise, buffer (seeing below).Aqueous solution also can comprise antiinflammatory and/or anti-histamine activity composition (be mentioned component (iii)), and add polar lipid or its mixture in the aqueous solution of antiinflammatory in the above-mentioned steps (a) and/or anti-histamine activity composition this moment.
Preferably, the step of said method (a) is finished under suitable stirring (for example stirring) condition.
Preferably, for example (for example pass through adding acid or alkali before homogenizing of above-mentioned steps (b), suitable concn (for example, hydrochloric acid 1M) and/or sodium hydroxide) with the pH regulator of preparation to desired value: about pH4 (for example 4.0) is to about pH 8 (for example 8.0), and preferably about pH 5 (for example 5.0) is about pH 7 (for example 7.0) extremely.
Preferably, for example before the homogenizing of above-mentioned steps (b) and/or after the above-mentioned pH regulator step, water, saline solution or buffer solution are added preparation, the final batch volume that obtains expecting.
And if when suitable, can be at the suitable stage of said method with nitrogen or argon with solution/liquid degassing.
In the context of the present invention, lipid can be in aqueous medium swellable, if it is contacted with such medium, its swellable is to the degree that can measure.
Preferably, before adding lipid, buffer can be joined in the aqueous solution of medicine (and/or medicine can be joined in the aqueous buffer solution).
Liposome of the present invention forms by following method and promotes: by polar lipid spontaneous swelling in water, form the lamellar liquid crystalline phase of the water content with (depending on polar lipid character) the highest about 35% weight or higher.According to the lipid that uses or lipid mixture and other condition, when adding excessive water in giving this lamellar phase, the spontaneity that can obtain this liposome forms (spontaneousformation).If do not obtain spontaneous formation, the preparation of this liposome can realize by in excessive water lamellated liquid-crystalline phase being carried out mechanical dispersion step (being the homogenization step (b) of said method).
Homogenize/process for dispersing comprises powerful mechanical mixture or high-speed homogenization, for example by UltraTurrax (Jankel ﹠amp; K ü hnke, method Germany).Also can carry out jolting, vortex and rolling, it is as the part of the homogenization step of said method.
The uniform grading of liposome of the present invention distributes and can expect, and can be by the membrane filter extruding for about 100nm obtains from the aperture, and described membrane filter is for example by polycarbonate.Membrane filter can be available from Avestin Inc., Canada.
Preferably, when the Liposomal dispersion process is used suitable homogenizer (Rannie APV, type7.30 VH, Rannie AS, Denmark) high pressure homogenizing about 4 is to about 8 (for example 7, for example 6) when inferior, average liposome particle diameter that can obtain reducing and narrow liposome particle size distribution, for example homogenize at about 300bar to about 1000bar, for example at about 400bar about 900bar extremely, for example about 500 to about 800bar.
We find to exist certain active component can cause reducing of liposome particle diameter.Less liposome is normally favourable, because it is in fact more stable, and because their higher surface area/volume ratio rate, they are easier in mucosa absorption.
The diameter of liposome is less than about 200nm (for example about 40 to about 100nm) in our the preferred present composition, and it is measured by for example laser diffraction described below or dynamic light scattering.
In addition, the said method of the preparation present composition does not for example need with an organic solvent chloroform or dichloromethane to carry out conventional treatment usually.Yet if use two or more membrane lipids, it is suitable and/or necessary handling them with organic solvent before adding aqueous solvent.For example, lipid can be dissolved in volatile solvent or the solvent mixture, for example chloroform or chloroform/methanol.This solution can be stored in the surface of round-bottomed flask then, the decompression rotary evaporation removes and desolvates.The excessive aqueous buffer solution that comprises medicine can be joined exsiccant lipid membrane then, make its swelling form liposome afterwards.In other cases, if active component obviously can not water-soluble and/or phospholipid, have and necessaryly before adding water, itself and phospholipid are dissolved in organic solvent.In addition, before adding water, organic solvent can be removed (for example, in a vacuum).
The present composition can be used for treating to the effective any indication of known relevant active component, for example in particular for Martindale " The Complete medicine Reference ", 34
ThEdition, among the RoyalPharmaceutical Society (2005) active component of those listed discussion at indication.
According to another aspect of the present invention, provide the method for treatment inflammatory diseases (and/or migraine or pain (for example, acute pain), depend on the circumstances), comprise that administration suffers from or be easy to suffer from the present composition of people's medicine effective quantity of the sort of disease.
For avoiding feeling uncertain, " treatment " comprises treatment of conditions treatment and symptomatiatria, prevention or diagnosis.
Though the present composition can use by any known approach, comprise parenteral, local use and/or oral, usually can be by the mode administration of permeable membrane, more specifically.Per nasal, eye and pulmonary administration.For example, compositions of the present invention can be passed through the mode administration of nasal mist, nasal drop and/or eye drop.Also can give lung with compositions of the present invention with the dispenser of micropowder mist by nebulization.For nasal-cavity administration, can use the technological level device that is suitable for preparing the spraying of aqueous Liposomal dispersion.
Can prepare these preparations according to method standard and/or pharmaceutically useful.
When in the degree (for example pH value, particle diameter, temperature, pressure etc.) of this paper and amount (for example drug ratios of quantity, weight and/or the concentration of each component, liposome structure inner/outer, the absolute dosages of active component etc. in the component of compositions or compositions) content, making word " pact ", can be regarded as such variable for being approximately the specifically described quantity of this paper, this quantity can change ± and 10%, for example ± 5%, preferred ± 2% (for example ± 1%).
The present composition and be used for the said method of their preparation has aforesaid advantage.Particularly, the present composition can reduce the incidence rate with for example common observed side effects of nasal cavity administrated preparation (especially stimulating).
The present composition is easy to preparation, and can make the liposome based formulation of type of service at once, has avoided the needs of the preceding reconstruct of administration.
The present composition also has advantage: they can use definite process for preparing medicine preparation, and the material that uses has gone through can be used for food or medicine or regulated the material of body constitution.
The present composition also has following advantage: compare with pharmaceutical composition known in the art, no matter be used for the treatment of rhinitis and still be used for the treatment of other disease, the side effect that they can be more effective, toxicity is littler, acting duration is longer, drug effect is stronger, produce is littler, easier to be absorbed and/or to have better pharmaco-kinetic properties, and/or has other useful pharmacology, physics or chemical characteristic.
The present invention can set forth by following embodiment.
Universal method.Weigh and the following form of standardize solution reference.In the 200mL volumetric flask, anhydrous citric acid and solid sodium hydroxide are dissolved in preparation buffer solution in the 160mL water (always criticize volume 80%).Add the active agent of weighing, use the magnetic stirrer stirring and dissolving.The phospholipid of weighing separately joins in the solution.Continuous stirring to the suspension that forms fine dispersion, is regulated pH to 5.0 ± 0.1 with 1.0M NaOH and/or 1.0M HCl.Criticize volume then the volume of standardize solution preparation to the end of 200mL.With preparation be transferred to the high pressure homogenizing device (Rannie APV, type 7.30 VH, Rannie AS, Denmark) in, in 500-800bar 5 circulations that homogenize.From collecting pipe, shift out the aliquot of the compositions that obtains then, be transferred in the vial.
Using above-mentioned steps is in order to prepare the final composition that following embodiment 1 to 8 lists.When suitable, the amount of composition is suitably amplified (for example, in embodiment 1 to 8, amplifying 200 times).The step of embodiment 9 is described in down separately.
Embodiment 1
| Budesonide phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) Benasept butylated hydroxytoluene (BHT) hydroxypropyl methylcellulose (Metolose 60SH-50) citric acid sodium hydroxide 1M HCl and/or 1M NaOH water for injection | ?1.3mg?35.0mg?0.1mg |
| ?0.1mg | |
| ?10mg | |
| ?19.2mg | |
| 8.4mg to pH 5.5 to 1mL |
Embodiment 2
| Fluticasone propionate phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) phospholipid (DMPC; Lipoid GmbH, Germany) Benasept butylated hydroxytoluene (BHT) citric acid sodium hydroxide 1M HCl and/or 1M NaOH water for injection | ?0.5mg?17.5mg?17.5mg |
| ?0.1mg | |
| ?0.1mg | |
| ?19.2mg | |
| 8.4mg to pH 5.5 to 1mL |
Embodiment 3
| Zileuton phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) phospholipid (DMPC; Lipoid GmbH, Germany) Benasept butylated hydroxytoluene (BHT) citric acid sodium hydroxide | ?200.0mg?23.3mg?11.7mg |
| ?0.1mg | |
| ?0.1mg | |
| ?19.2mg | |
| ?8.4mg |
| 1M HCl and/or 1M NaOH water for injection | To pH 5.5 to 1mL |
Embodiment 4
| Nitrogen Si spit of fland phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) phospholipid (DMPC; Lipoid GmbH, Germany Benasept butylated hydroxytoluene (BHT) Polyethylene Glycol (Macrogol 6000) citric acid sodium hydroxide 1M HCl and/or 1M NaOH water for injection | ?0.9mg?23.3mg?11.7mg |
| ?0.1mg | |
| ?0.1mg | |
| ?10mg | |
| ?19.2mg | |
| 8.4mg to pH 5.5 to 1mL |
Embodiment 5
| Montelukast phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) phospholipid (DMPC; Lipoid GmbH, Germany Benasept butylated hydroxytoluene (BHT) polyvinylpyrrolidone citric acid sodium hydroxide 1M HCl and/or 1M NaOH water for injection | 25mg29.2mg5.8mg |
| 0.1mg | |
| 0.01mg | |
| 1.0mg | |
| 19.2mg | |
| 8.4mg to pH 5.5 to 1mL |
Embodiment 6
| Etoricoxib phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) | 150.0mg23.3mg |
| Phospholipid (DMPC; Lipoid GmbH, Germany Benasept butylated hydroxytoluene (BHT) hydroxypropyl methylcellulose (Metolose 60SH-50) citric acid sodium hydroxide 1M HCl and/or 1M NaOH water for injection | ?11.7mg |
| ?1.0mg | |
| ?0.1mg | |
| ?5.0mg | |
| ?19.2mg | |
| 8.4mg to pH 5.5 to 1mL |
Embodiment 7
| Budesonide phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) Benasept butylated hydroxytoluene (BHT) citric acid sodium hydroxide 1M HCl and/or 1M NaOH water for injection | 1.3mg 35.0mg 0.2mg 0.2mg 19.2mg 8.4mg to pH 5.0 is to 1mL |
Embodiment 8
| Fluticasone propionate phospholipid (Semen sojae atricolor; Lipoid S100; Lipoid GmbH, Germany) phospholipid (DMPC; Lipoid GmbH, Germany) sorbic acid Na EDTA butylated hydroxytoluene (BHT) citric acid sodium hydroxide 1M HCl and/or 1M NaOH water for injection | 0.5mg 27.0mg 8.0mg 1.0mg 0.1mg 0.2mg 19.2mg 8.4mg to pH 5.0 is to 1mL |
Embodiment 9
Commercial nose hydryllin nitrogen Si spit of fland (trade name of registration such as Azelvin
, Azosin
, Astelin
, Lastin
And Rhinolast
) use following amount and step to prepare.
1. the 160mL nose nitrogen Si spit of fland solution (Lastin that will contain 0.9mg/mL nitrogen Si spit of fland
) change the 200mL volumetric flask over to.
2. add 7g soybean phospholipid (Lipoid S100; Lipoid GmbH Germany), spends the night the mixture swelling.
3. add more nitrogen Si spit of fland solution volume is settled to 200mL (seeing above-mentioned steps 1).
4. check pH.
Described in above-mentioned general step, with solution in 800bar 7 circulations that homogenize.
Claims (80)
1. a pharmaceutical composition for the treatment of the homogenizing of inflammatory diseases comprises antiinflammatory and/or anti-histamine activity composition, polar lipid liposome and pharmaceutically acceptable aqueous carrier, and condition is that active component is not an alerlisin.
2. the compositions of claim 1, it comprises that further it is about 4 to about pH 8 pharmaceutically acceptable buffer that pH can be provided.
3. the compositions of claim 2, wherein the pH scope is about pH5 about pH7 extremely.
4. claim 2 or 3 compositions, wherein buffer is phosphate, citrate or acetate buffer.
5. the compositions of claim 4, wherein buffer is that sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid add alkali salt, sodiocitrate, citric acid and add alkali salt, acetic acid sodium salt or acetic acid add the alkali salt buffer.
6. each compositions in the claim 2 to 5, wherein the scope of amount of buffer is about 1mg/mL about 30mg/mL extremely.
7. each compositions in the aforementioned claim, wherein active component is a hydryllin.
8. the compositions of claim 7, wherein hydryllin is selected from acrivastine, alimemazine, anatazoline, astemizole, azatadine, nitrogen Si spit of fland, bamipine, bepotastine, bromazine, bromopheniramine, buclizine, carbinoxamine, chloreyclizine, chloropyramine, chlorophenamine, cinnarizine, clemastine, clemizole, clocinizine, cyclizine, Cyproheptadine, deptropine, Desloratadine, dexchlorpheniramine, dimenhydrinate, dimetindene, dimetotiazine, diphenhydramine, piphenylpyraline, doxylamine, ebastine, embramine, emedastine, epinastine, fexofenadine, flunarizine, homochlorocyclizine, hydroxyzine, isothipendyl, levocarbastine, loratidine, mebhydroline, meclizine, pyrilamine, mequitazine, methdilazine, mizolastine, niaprazine, olopatadine, oxatomide, oxomemazine, phenindamine, pheniramine, phenyltoloxamine, pimethixene, pipinhydrinate, promethazine, propiomazine, quifenadine, ruputadine, setastine, Compound Terfenadine Tablete, thenyldiamine, thiethylperazine, the thonzylamine, tolpropaminr, trimethobenzamine, tripelennamine, triprolidine, tritoqualine reaches the wherein officinal salt of any chemical compound.
9. each compositions in the claim 1 to 6, wherein active component is an anti-inflammatory drug.
10. the compositions of claim 9, wherein anti-inflammatory drug is the steroidal class.
11. the compositions of claim 10, wherein the steroidal class is selected from alclometasone, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, deflazacort, dexamethasone, nerisona, fluocinonide, fluocinolone acetonide, fluocortolone, fluprednidene, flurometholone, fluticasone, halcinonide, hydrocortisone, methylprednisolone, mometasone, prednisolone, rimexolone, and triamcinolone reaches the wherein officinal salt of any chemical compound.
12. the compositions of claim 9, wherein anti-inflammatory drug is a nonsteroidal anti-inflammatory drug.
13. the compositions of claim 12, wherein nonsteroidal anti-inflammatory drug is the PDE4 inhibitor.
14. the compositions of claim 12, wherein nonsteroidal anti-inflammatory drug is the leukotriene trim.
15. the compositions of claim 14, wherein the leukotriene trim is the 5-lipoxidase inhibitor.
16. the compositions of claim 14, wherein the leukotriene trim is the FLAP inhibitor.
17. the compositions of claim 14, wherein the leukotriene trim is the CysLT antagonist.
18. each compositions in the aforementioned claim, wherein polar lipid is a natural origin, synthetic/semi-synthetic source or its mixture.
19. each compositions in the aforementioned claim, wherein polar lipid comprises or is made up of phospholipid or mixture of phospholipids.
20. the compositions of claim 19, wherein phospholipid comprises or its mixture in phosphatidylcholine, phosphatidyl glycerol, phosphatidylinositols, phosphatidic acid, the Phosphatidylserine.
21. the compositions of claim 19 or 20, wherein phospholipid comprises the chemical compound that general formula I is represented,
R wherein
1And R
2Expression has the saturated or unsaturated branched-chain or straight-chain alkyl of 7 to 23 carbon atoms independently; R
3Expression amide or ester are in conjunction with base.
22. the compositions of claim 21, wherein amide or ester linking group are-CH
2-CH (OH)-CH
2OH ,-CH
2-CH
2-N (CH
3)
3,-CH
2-CH
2-NH
2,-H or-CH
2-CH (NH
2)-COOH.
23. each compositions in the claim 19 to 22, wherein phospholipid comprises the membrane lipid that is derived from Semen sojae atricolor.
24. the compositions of claim 23, wherein phospholipid comprises Lipoid S75, Lipoid S100 and/or Lipoid S75-3N.
25. each compositions in the claim 19 to 24, wherein phospholipid comprises dilauryl phosphatidylcholine, myristyl phosphatidylcholine, two palmityl phosphatidylcholines, two Laurel acyl phospholipids acyl glycerol, myristyl phosphatidyl glycerol, dioleyl phosphatidyl choline and dioleoyl phosphatidyl glycerol.
26. each compositions in the claim 1 to 18, wherein polar lipid comprises or is made up of glycolipid or its mixture.
27. the compositions of claim 26, wherein glycolipid comprises glycosyl glyceride matter.
28. the compositions of claim 27, wherein glycosyl glyceride matter comprises the galactose glyceride.
29. the compositions of claim 27, wherein glycosyl glyceride matter comprises the digalactosylglycerol fat of general formula I I,
R wherein
1And R
2Such as claim 21 definition.
30. the sharp combination property rights that require in 26 to 29 each, wherein glycolipid comprises digalactosylglycerol fat.
31. the compositions of claim 26, wherein glycolipid comprises glycosyl sphingolipid.
32. the compositions of claim 31, wherein glycosyl sphingolipid comprises single glycosyl sphingolipid, oligomeric glycosyl sphingolipid, oligomeric glycosyl ceramide, monoglycosylceramide, sialoglycosphingolipids, uronoglycosphingolipids, sulfo group glycosyl sphingolipid, phosphoric acid glycosyl sphingolipid and phosphono glycosyl sphingolipid, ceramide, single hexose ceramide, two hexose ceramides, sphingomyelins, lysosphingomyelin, sphingol or its mixture.
33. the compositions of claim 32, wherein glycosyl sphingolipid comprises the sphingomyelins or derivatives thereof.
34. the compositions of claim 26, wherein glycolipid comprises glycophosphatidyl inositol.
35. each compositions in the aforementioned claim, wherein the amount of compositions Semi-polarity lipid is that about 10mg/mL is to about 120mg/mL.
36. each compositions in claim 1 to 25 or 35, wherein the amount of phospholipid is that about 17mg/mL is to about 70mg/mL in the compositions.
37. the compositions of claim 36, wherein amount is that about 20mg/mL is to about 40mg/mL.
38. each compositions in the aforementioned claim, it further comprises antioxidant.
39. the compositions of claim 38, wherein antioxidant is alpha-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaric acid, malic acid, monothioglycerol, propanoic acid, propyl gallate, sodium ascorbate, sodium sulfite, sodium pyrosulfite, potassium metabisulfite, sodium sulfite, tartaric acid or vitamin E.
40. each compositions in the aforementioned claim, it further comprises chelating agen.
41. the compositions of claim 40, wherein chelating agen is ethylenediaminetetraacetic acid (and/or its salt), ethylenediamine triacetic acid and/or diethylene-triamine pentaacetic acid (DTPA).
42. each compositions in the aforementioned claim, it further comprises antiseptic.
43. the compositions of claim 42, wherein antiseptic is Benasept, benzoic acid, butylated hydroxyanisole, butoben, methaform, ethyl hydroxybenzoate, methyl hydroxybenzoate, propylparaben, phenoxyethanol or phenethanol.
44. each compositions in the aforementioned claim, it further comprises viscosifier.
45. the compositions of claim 44, wherein viscosifier are Polyethylene Glycol, crospolyvinylpyrrolidone and/or hydroxypropyl methylcellulose.
46. each compositions in the aforementioned claim, wherein the diameter of liposome is less than about 200nm.
47. the compositions of claim 46, wherein diameter is that about 40nm is between about 100nm.
48. a method for compositions for preparing in the aforementioned claim each comprises:
(a) with (i) polar lipid or mixture, it is swellable in aqueous medium, and (ii) water is with (iii) antiinflammatory and/or anti-histamine activity composition mix; And
(b) preparation that homogenizes.
49. the method that claim 48 requires is wherein in the aqueous solution with antiinflammatory in polar lipid or its mixture adding above-mentioned steps (a) and/or anti-histamine activity composition.
50. the methods that claim 48 or 49 requires wherein, transferred to pH the value of expectation by adding acid or alkali before homogenizing.
51. each method of claim 48 to 50, wherein, before homogenizing by adding the final batch volume that entry, saline or buffer solution must be expected.
52. the method (on the basis of claim 50) that claim 51 requires, wherein the adding step of water, saline or buffer is after transferring the pH step.
53. each method of claim 48 to 52, wherein at least a solution/liquid is with nitrogen and/or argon-degassed.
54. each method of claim 49 to 53, wherein before adding phospholipid, the formation of the aqueous solution of active component or by buffer is added in the aqueous solution of active component, or active component is added in the aqueous buffer solution.
55. each method of claim 48 to 54, wherein, if use polar lipid mixtures, with the organic solvent pretreatment.
56. each method of claim 48 to 54, wherein, if active component is obviously water insoluble, with organic solvent pretreatment (unite and use lipid).
57. each method of claim 48 to 56, wherein homogenization step (b) comprises powerful mechanical mixture, high-speed homogenization, jolting, vortex and/or rolling.
58. each method of claim 48 to 57, it comprises the other step that reduces the liposome particle diameter.
59. comprising, the method that claim 58 requires, the step that wherein reduces particle diameter be pressed through filter membrane.
60. claim 48 to 56,58 or 59 each methods, wherein homogeneity step and/or reduce the particle diameter step and comprise high pressure homogenizationization.
61. pharmaceutical composition, its acquisition methods comprise the steps or are made up of following step basically:
(a) with (i) polar lipid or mixture, it is swellable in aqueous medium, and (ii) water is with (iii) antiinflammatory and/or anti-histamine activity composition mix; And
(b) preparation that homogenizes.
62. the compositions of claim 61, wherein, in the aqueous solution with antiinflammatory in polar lipid or its mixture adding above-mentioned steps (a) and/or anti-histamine activity composition in preparation.
63. the compositions of claim 61 or 62 wherein, transferred to pH the value of expectation by adding acid or alkali before homogenizing.
64. each compositions in the claim 61 to 63, wherein, before homogenizing by adding the final batch volume that entry, saline or buffer solution must expect.
65. the compositions of claim 64 (on the basis of claim 63), wherein the adding step of water, saline or buffer is after transferring the pH step.
66. each compositions in the claim 61 to 65, wherein at least a solution/liquid is with nitrogen and/or argon-degassed.
67. each compositions in the claim 62 to 66, wherein before adding phospholipid, the formation of the aqueous solution of active component or by buffer is added in the aqueous solution of active component, or active component is added in the aqueous buffer solution.
68. each compositions in the claim 61 to 67, wherein, if use polar lipid mixtures, with the organic solvent pretreatment.
69. each compositions in the claim 61 to 67, wherein, if active component is obviously water insoluble, with organic solvent pretreatment (unite and use lipid).
70. each compositions in the claim 61 to 69, wherein, homogenization step (b) comprises powerful mechanical mixture, high-speed homogenization, jolting, vortex and/or rolling.
71. each compositions in the claim 61 to 70, it comprises the other step that reduces the liposome particle diameter.
72. comprising, the compositions of claim 71, the step that wherein reduces particle diameter be pressed through filter membrane.
73. claim 61 to 69, each compositions in 71 or 72, wherein, homogeneity step and/or reduce the particle diameter step and comprise high pressure homogenizationization.
74. claim 1 to 47, or each compositions in 61 to 73 are used for medical science.
75. a method for the treatment of inflammatory diseases comprises claim 1 to 47, or each compositions is applied to and suffers from or easily suffer from this sick patient in 61 to 73.
Suffer from or easily suffer from this sick patient 76. claim 1 to 47, or each the purposes of compositions in the medicine of preparation treatment inflammatory diseases in 61 to 73, this treatment comprise compositions is applied to.
77. the method that claim 75 requires, or the purposes of claim 76 requirement, wherein inflammatory diseases is a rhinitis.
78. the method that claim 75 requires, or the purposes of claim 76 requirement, wherein inflammatory diseases is an asthma.
79. the method that claim 75 requires, or the purposes of claim 76 requirement, wherein inflammatory diseases is an inflammatory pain.
80. claim 75 or 77 to 79 each methods, or claim 76 or 77 to 79 purposes that require, wherein compositions is the via intranasal application administration.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68869805P | 2005-06-09 | 2005-06-09 | |
| US60/688,698 | 2005-06-09 | ||
| US60/696,777 | 2005-07-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101193622A true CN101193622A (en) | 2008-06-04 |
Family
ID=35478745
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800205359A Pending CN101193622A (en) | 2005-06-09 | 2006-06-08 | Method and composition for treating inflammatory disorders |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101193622A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102257387A (en) * | 2008-10-28 | 2011-11-23 | 巴黎公众助理医院 | Methods and kits for the rapid determination of patients at high risk of death during severe sepsis and septic shock |
| CN102858176A (en) * | 2010-03-10 | 2013-01-02 | 加林制药公司 | Analgesic compounds, compositions, and uses thereof |
| CN103860561A (en) * | 2014-04-08 | 2014-06-18 | 青岛大学医学院附属医院 | Medicament composition for preventing and treating breast cancer and application thereof |
| CN106632562A (en) * | 2015-10-30 | 2017-05-10 | 天津法莫西医药科技有限公司 | Refinement technique of fluorometholone |
| CN107812004A (en) * | 2017-11-24 | 2018-03-20 | 南京中医药大学 | The application of Desloratadine and its pharmaceutically acceptable salt in the medicine for preparing treatment Alzheimer disease |
| CN107922404A (en) * | 2015-06-30 | 2018-04-17 | 艾格集团国际公司 | Chloroquine and clemizole compound are used for the purposes for treating inflammation and cancer |
| CN109069501A (en) * | 2016-03-18 | 2018-12-21 | H4奥芬制药 | H4 agonist molecule is used to treat the purposes of idiopathic pulmonary fibrosis |
| CN110870864A (en) * | 2018-08-29 | 2020-03-10 | 复旦大学 | Application of carbinoxamine maleate in preparation of anti-influenza virus medicine |
-
2006
- 2006-06-08 CN CNA2006800205359A patent/CN101193622A/en active Pending
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102257387A (en) * | 2008-10-28 | 2011-11-23 | 巴黎公众助理医院 | Methods and kits for the rapid determination of patients at high risk of death during severe sepsis and septic shock |
| CN102858176A (en) * | 2010-03-10 | 2013-01-02 | 加林制药公司 | Analgesic compounds, compositions, and uses thereof |
| CN103860561A (en) * | 2014-04-08 | 2014-06-18 | 青岛大学医学院附属医院 | Medicament composition for preventing and treating breast cancer and application thereof |
| CN103860561B (en) * | 2014-04-08 | 2015-11-18 | 青岛大学医学院附属医院 | A kind of pharmaceutical composition and application thereof preventing and treating breast carcinoma |
| US10688083B2 (en) | 2015-06-30 | 2020-06-23 | Eiger Group International, Inc. | Use of chloroquine and clemizole compounds for treatment of inflammatory and cancerous conditions |
| IL279020B2 (en) * | 2015-06-30 | 2023-07-01 | Eiger Group Int Inc | Use of chloroquine and clemizole compounds for treatment of inflammatory and cancerous conditions |
| CN107922404A (en) * | 2015-06-30 | 2018-04-17 | 艾格集团国际公司 | Chloroquine and clemizole compound are used for the purposes for treating inflammation and cancer |
| IL279020B1 (en) * | 2015-06-30 | 2023-03-01 | Eiger Group Int Inc | Use of chloroquine and clemizole compounds for treatment of inflammatory and cancerous conditions |
| CN106632562A (en) * | 2015-10-30 | 2017-05-10 | 天津法莫西医药科技有限公司 | Refinement technique of fluorometholone |
| CN106632562B (en) * | 2015-10-30 | 2020-02-18 | 天津法莫西医药科技有限公司 | Fluorometholone refining process |
| CN109069501B (en) * | 2016-03-18 | 2021-09-17 | H4奥芬制药 | Use of H4 agonist molecules for the treatment of idiopathic pulmonary fibrosis |
| CN109069501A (en) * | 2016-03-18 | 2018-12-21 | H4奥芬制药 | H4 agonist molecule is used to treat the purposes of idiopathic pulmonary fibrosis |
| WO2019100603A1 (en) * | 2017-11-24 | 2019-05-31 | 南京中医药大学 | Applications of desloratadine and pharmaceutically acceptable salt thereof in preparation of drugs for treating alzheimer disease |
| CN107812004A (en) * | 2017-11-24 | 2018-03-20 | 南京中医药大学 | The application of Desloratadine and its pharmaceutically acceptable salt in the medicine for preparing treatment Alzheimer disease |
| CN110870864A (en) * | 2018-08-29 | 2020-03-10 | 复旦大学 | Application of carbinoxamine maleate in preparation of anti-influenza virus medicine |
| CN110870864B (en) * | 2018-08-29 | 2021-09-24 | 复旦大学 | Application of carbinoxamine maleate in preparation of anti-influenza virus medicine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2006256518B2 (en) | Method and composition for treating inflammatory disorders | |
| CN101193622A (en) | Method and composition for treating inflammatory disorders | |
| JP6966981B2 (en) | Anticonvulsant activity of steroids | |
| CN101257891A (en) | Antihistamine- and corticosteroid- containing liposome composition and its use for the manufacture of a medicament for treating rhinitis and related disorders | |
| RU2762725C2 (en) | Compositions containing triptane compounds | |
| Shinkar et al. | Drug delivery from the oral cavity: A focus on mucoadhesive | |
| CN109640981A (en) | Neurokinine-1 antagonist is used to treat the purposes of a variety of pruritic conditions | |
| CN104983669B (en) | tablet containing steroid hormone | |
| CN1984643A (en) | Method and composition for treating rhinitis | |
| TW200306801A (en) | Farnesoid X-activated receptor agonists | |
| TW200800223A (en) | Transdermal delivery of meptazinol | |
| CN103784423A (en) | Flavoring of drug-containing chewing gums | |
| CN115003279A (en) | Prodrug compositions and methods of treatment | |
| TW537893B (en) | A pharmaceutical composition for the prevention of migraine recurrence | |
| CN115135323A (en) | Pharmaceutical composition | |
| EP3787631A1 (en) | Modulators of orphan nuclear receptors for nash and other metabolic disorders | |
| JP2935113B1 (en) | Indomethacin transdermal absorbent | |
| TW201202232A (en) | Treatment of GIST with masitinib | |
| WO2023186963A1 (en) | Combination of nitrous oxide and 5-ht2a receptor agonists | |
| CN116940351A (en) | Prodrug compositions and methods of treatment | |
| WO2000048999A1 (en) | Morphan derivatives or salts thereof and medicinal compositions containing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: MEDA CO., LTD. Free format text: FORMER OWNER: BIOLIPOX AB Effective date: 20120327 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20120327 Address after: Solna, Sweden Applicant after: MEDA limited liability company Address before: Solna, Sweden Applicant before: Biolipox AB |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20080604 |