Kit for the preparation of a pharmaceutical composition

• US 20040247628A1
• Filed: 04/23/2004
• Published: 12/09/2004
• Est. Priority Date: 10/24/2001
• Status: Abandoned Application

• Current Assignee: PARI Pharma GmbH (PARI MEDICAL HOLDING GmbH)
• Original Assignee: PARI Pharma GmbH (PARI MEDICAL HOLDING GmbH)
• Inventors: Lintz, Frank-Christophe, Keller, Manfred
• Application Number:
  US10/493,687
• Publication Number:
  US 20040247628A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics

Abstract

The invention relates to pharmaceutical kits for the preparation of liquid compositions which can be administered to humans as aerosols for the diagnosis, prevention or treatment of human diseases. A kit according to the invention comprises a solid composition and a sterile aqueous liquid capable of dispersing or dissolving the solid composition to form a liquid composition which can be aerosolized. The solid composition of the kit comprises one or more active compounds and a water-soluble, low molecular weight excipient. Preferably, the solid composition comprises a sugar or a sugar alcohol, such as mannitol, lactose, or glucose.

Claims

1-36. -36. (cancelled)

37. A kit for preparing a liquid pharmaceutical composition for pulmonary administration, the kit comprising:

(a) a solid composition comprising an active compound and at least one pharmaceutically acceptable water-soluble excipient, said excipient having a molecular weight of no more than 1000 and a water solubility of at least 10 wt.-% at room temperature;

(b) a sterile aqueous liquid capable of dissolving the solid composition to form said liquid pharmaceutical composition.

38. The kit of claim 37, wherein the water-soluble excipient has a molecular weight of less than 500 and/or a water solubility of at least 20 wt.-% at room temperature.

39. The kit of claim 38, wherein the water-soluble excipient is selected from the group consisting of mono- and disaccharides, sugar alcohols, organic or inorganic salts, organic or inorganic acids, and amino acids.

40. The kit of claim 39, wherein the water-soluble excipient is selected from the group consisting of mannitol, lactose, and glucose.

41. The kit of claim 37, wherein the concentration of the water-soluble excipient in the solid composition is from about 10 wt.-% to about 99.5 wt.-%.

42. The kit of claim 37, wherein the solid composition comprises at least two pharmaceutically acceptable water-soluble excipients having a molecular weight of no more than 1000 and a water solubility of at least 10 wt.-% at room temperature.

43. The kit of claim 37, wherein the solid composition and the sterile aqueous liquid are accommodated in separate containers.

44. The kit of claim 43, comprising multiple doses of the active compound.

45. The kit of claim 44, wherein the sterile aqueous liquid is contained in a metered dose dispenser.

46. The kit of claim 37, wherein the solid composition and the sterile aqueous liquid are accommodated in separate chambers of the same container.

47. The kit of claim 46, comprising one single dose of the active compound.

48. The kit of claim 47, comprising a blister pack having a narrowed portion forming a tip, said pack comprising:

(a) a first blister chamber containing a solid composition, said composition comprising an active compound and at least one pharmaceutically acceptable water-soluble excipient;

(b) a second blister chamber containing a sterile aqueous liquid capable of dissolving said solid composition to form a liquid composition for nasal or pulmonary administration;

(c) a first channel extending from the first to the second blister chamber, said first channel being closed with a breakable or removable seal; and

(d) a second channel extending from the first or the second blister chamber to a distal position of the tip,

wherein the contents of the first and second blister chambers can be mixed by perforation of the connecting seals of both chambers by means of external pressure and wherein one of the blister chambers may contain a glass sphere, ring or any aid facilitating the perforation of the seal.

49. The kit of claim 48, further comprising a breakable or removable closure positioned at the distal end of the second channel.

50. The kit of claim 37, wherein the solid composition is substantially free of polymers.

51. The kit of claim 37, wherein the solid composition further comprises a surfactant.

52. The kit of claim 51, wherein the surfactant is selected from the group consisting of tyloxapol, Tween 80, and phospholipids.

53. The kit of claim 37, wherein the solid composition is in the form of a single unit.

54. The kit of claim 53, wherein the solid composition is in the form of a lyophilized matrix.

55. The kit of claim 53, wherein the solid composition a compressed tablet.

56. The kit of claim 53, wherein the solid composition is film- or foil-shaped.

57. The kit of claim 37, wherein the solid composition is in the form of multiple units.

58. The kit of claim 57, wherein the solid composition comprises a lyophilized powder.

59. The kit of claim 57, wherein the solid composition is a soluble coating layer which is coated on a multiple unit carrier.

60. The kit of claim 59, wherein the multiple unit carrier is insoluble.

61. The kit of claim 59, wherein the multiple unit carrier consists of beads made from a material selected from the group consisting of glass, polymers, metals, and mineral salts.

62. The kit of claim 59, wherein the multiple unit carrier is soluble.

63. The kit of claim 59, wherein the soluble coating further comprises a binder, such as a saccharide, a sugar alcohol, or a film-forming polymer.

64. The kit of claim 37, wherein the aqueous liquid is capable of dissolving the solid composition within 30 seconds.

65. The kit of claim 37, wherein the aqueous liquid and the solid composition are formulated to form a liquid pharmaceutical composition having an osmolality from about 150 mOsmol/kg to about 600 mOsmol/kg.

66. The kit of claim 37, wherein the aqueous liquid and the solid composition are formulated to form a liquid pharmaceutical composition having a pH from about 3.5 to about 10.5.

67. The kit of claim 37, wherein the aqueous liquid and/or the solid composition comprises a buffer or a buffer salt, and wherein the aqueous liquid and the solid composition are formulated to form a liquid pharmaceutical composition having a buffer capacity _β

from about 0.01 to about 0.7.

68. The kit of claim 37, wherein the active compound is unstable in an aqueous environment.

69. A method of treating a mammal suffering from or susceptible to a disease or condition affecting the respiratory system, comprising administering to the mammal a composition of the kit of claim 37.

70. The method of claim 69 wherein the mammal is suffering from or susceptible to bronchitis, asthma, chronic obstructive pulmonary disease, allergies, cystic fibrosis, pneumonia, bronchiectasis, bronchiolitis, lung cancer, fibrosis, pulmonary hypertension, respiratory distress syndrome, bacterial or viral infection, tuberculosis or sinusitis.

71. The method of claim 69 wherein the composition is administered through the nose and/or lungs of the mammal.

72. The kit of claim 37 wherein the active compound is selected from the group consisting of substances for diagnostic purposes such as metacholin or antiasthmatics, comprising beta-agonists, such as salbutamol, levalbuterol, formoterol, fenoterol, salmeterol, bambuterol, brocaterol, clenbuterol, terbutalin, tulobuterol, epinephrin, isoprenalin, orciprenalin, hexoprenalin;

anticholinergics, such as tiotropium, oxitropium, ipratropium, glycopyrrolate;

local anaesthetics, such as lidocain and derivatives thereof, mucolytics and surfactants, such as acetylcystein, ambroxol, carbocystein, tyloxapol, dipalmytoylphosphatidylcholin, recombinant surfactant proteins, D-nase;

anti-inflammatory drugs comprising mediator cell inhibitors, such as cromoglycate, nedocromil, lidocaine, elastane-, leucotriene-, bradykinin-antagonists;

corticosteroids, such as beclomethasone, betamethasone, budesonide, ciclesonide, flunisolide, fluticasone, icomethasone, mometasone, rofleponide, triamcinolone;

bradykinine-, prostaglandine-, leucotriene- and platelet activating factor antagonists;

antibiotics, including beta-lactam antibiotics, such as amoxicillin, piperacillin, clavulan acid, sulbactam;

cephalosporines, e.g. cefaclor, cefazedon, Cefuroxim, Cefoxitin, cefodizim, cefsulodin, cefpodixim, cefixim;

carbapenemes, such as imipenem and cilastatin;

further monbactames, e.g aztrenonam;

aminoglycosides, such as streptomycin, neomycin, colistin, paromomycin, kanamycin, gentamycin, amicacin, tobramycin, spectinomycine;

tetracyclines, such as doxycyclin, minocycline;

makrolides, such as erythromycine, clarithromycine, roxithromycine, azithromycine, josamycine, spiramycine;

gyrase inhibitors or quinolones, such as ciprofloxacin, ofloxacine, levofloxacine, pefloxacine, lomefloxacine, fleroxacine, clinafloxacine, sitafloxacine, gemifloxacine, balofloxacine, trovafloxacine, gatifloxacine, moxifloxacine;

sulfonamides and nitroimidazoles, including metronidazol, timidazol, chloramphenicol, lincomycine, clindamycine, fosfomycine;

glycopeptides such as vancomycine, teicoplanine;

peptide antibiotics, such as peptide 4;

tuberculostatics, e.g. rifampicine, isoniacide, cycloserine, terizidone, ansamycine;

antimycotics and antifungals, such as clotrimazol, oxiconazol, miconazol, ketoconazol, itraconazol, fluconazol;

polyene antibiotics, such as amphotericine B, natamycine, nystatine, terbinafine, colistine, flucytosine;

chemotherapeutics like pentamidine;

immunesuppressors and immunemodulators, cytokines, dimepranol-4-acetate amideo benzoate, thymopentin, interferones, filgrastine, interleukine, azathioprine, ciclosporine, tacrolimus, sirolimus, rapamycine;

drugs to treat pulmonary hypertension, such as prostacycline analogs, iloprost, remodulin, phosphodiesterase inhibitors, such as sildenafil, vardenafil, endothelian receptor antagonists, such as bosentane, tezosentane, virustatics, including podophyllotoxine, vidarabine, tromantadine, zidovudine;

proteinase inhibitors, such as a-anti-trypsin;

antioxidants, such as tocopherols, glutathion;

pituitary hormones, hypothalamic hormones, regulatory peptides and their inhibiting agents, corticotropine, tetracosactide, choriogonandotropine, urofolitropine, urogonadotropine, saomatotropine, metergoline, desmopressine, oxytocine, argipressine, ornipressine, leuproreline, triptoreline, gonadoreline, busereline, nafareline, goselerine, somatostatine;

parathyroide gland hormones, calcium metabolism regulators, dihydrotachysterole, calcitonine, clodronic acid, etidronic acid;

thyroid gland therapeutics;

sex hormones and their inhibiting agents, anabolics, androgens, estrogens, gestagenes, antiestrogenes;

cytostatics and metastasis inhibitors, alkylants, such as nimustine, melphanlane, carmustine, lomustine, cyclophosphosphamide, ifosfamide, trofosfamide, chlorambucil, busulfane, treosulfane, prednimustine, thiotepa;

antimetabolites, e.g. cytarabine, fluorouracil, methotrexate, mercaptopurine, tioguanine;

alkaloids, such as vinblastine, vincristine, vindesine;

antibiotics, such as alcarubicine, bleomycine, dactinomycine, daunorubicine, doxorubicine, epirubicine, idarubicine, mitomycine, plicamycine;

complexes of secondary group elements (e.g. Ti, Zr, V, Nb, Ta, Mo, W, Pt) such as carboplatinum, cis-platinum and metallocene compounds such as titanocendichloride;

amsacrine, dacarbazine, estramustine, etoposide, beraprost, hydroxycarbamide, mitoxanthrone, procarbazine, temiposide;

anti-migraine drugs, such as proxibarbal, lisuride, methysergide, dihydroergotamine, ergotamine, clonidine, pizotifene;

hypnotics, sedatives, benzodiazepines, barbiturates, cyclopyrrolones, imidazopyridines, antiepileptics, barbiturates, phenyloin, primidone, mesuximide, ethosuximide, sultiam, carbamazepin, valproic acid, vigabatrine;

antiparkinson drugs, such as levodopa, carbidopa, benserazide, selegiline, bromocriptine, amantadine, tiapride;

antiemetics, such as thiethylperazine, bromopride, domperidone, granisetrone, ondasetrone, tropisetrone, pyridoxine;

analgesics, such as buprenorphine, fentanyl, morphine, codeine, hydromorphone, methadone, fenpipramide, fentanyl, piritramide, pentazocine, buprenorphine, nalbuphine, tilidine;

drugs for narcosis, such as N-methylated barbiturates, thiobarbiturates, ketamine, etomidate, propofol, benzodiazepines, droperidol, haloperidol, alfentanyl, sulfentanyl;

antirheumatism drugs including tumor necrosis factor-alfa, nonsteroidal antiinflammatory drugs;

antidiabetic drugs, such as insulin, sulfonylurea derivatives, biguanids, glitizols, glucagon, diazoxid;

cytokines, such as interleukines, interferones, tumor necrosis factor (TNF), colony stimulating factors (GM-CSF, G-CSF, M-CSF);

proteins, e.g. epoetine, and peptides, e.g. parathyrin, somatomedin C;

heparine, heparinoids, urokinases, streptokinases, ATP-ase, prostacycline, sexual stimulants, or genetic material.

73. The kit of claim 37 wherein the active compound is selected from the group consisting of substances for diagnostic purposes;

beta-agonists;

anticholinergics;

local anaesthetics;

mucolytics and surfactants;

anti-inflammatory drugs;

antibiotics;

tetracyclines;

sulfonamides;

nitroimidazoles;

glycopeptides;

peptide antibiotics;

tuberculostatics;

ansamycine;

antimycotics;

antifungals;

polyene antibiotics;

chemotherapeutics;

drugs to treat pulmonary hypertension;

phosphodiesterase inhibitors;

endothelian receptor antagonists;

proteinase inhibitors;

antioxidants;

pituitary hormones;

hypothalamic hormones;

regulatory peptides and their inhibiting agents;

parathyroide gland hormones;

calcium metabolism regulators;

thyroid gland therapeutics;

sex hormones and their inhibiting agents;

anabolics; and

rogens;

estrogens;

gestagenes;

antiestrogenes;

cytostatics;

metastasis inhibitors;

alkylants;

antimetabolites;

alkaloids;

complexes of secondary group elements;

metallocene compounds;

anti-migraine drugs;

antiepileptics;

barbiturates;

antiparkinson drugs;

antiemetics;

analgesics;

drugs for narcosis;

antirheumatism drugs;

nonsteroidal antiinflammatory drugs;

antidiabetic drugs;

cytokines;

proteins;

peptides;

or sexual stimulants.

74. The kit of claim 37 wherein the active compound is selected from the group consisting of albuterol, salbutamol, R-salbutamol, bitolterol, carbuterol, tretoquinol, formoterol, clenbuterol, reproterol, pirbuterol, tulobuterol, procaterol, bambuterol, mabuterol, tiaramide, budenoside, fluticasone, beclometasone, deflazacort, TBI-PAB, flunisolide, cloprednol, emedastine, epinastine, oxatomide, azelastine, pemirolast, repirinast, suplatast, nedocromil, oxitropium, flutropium, triamcinolone, allergy vaccines, zafirlukast, montelukast, ramatroban, seratrodast, TJ-96, ibudilast, tranilast, Iodoxamide, TO-194, pranlukast, letosteine, ketotifen, amlexanox, zileuton, Efamol Marine, tazanolast, ribavirin, pentamidine, colistin, amphotericin B, ozagrel, including their derivatives, salts, conjugates, isomers, epimers, diastereomers, or racemic mixtures.

75. The kit of claim 37 further comprising an effervescent couple consisting two reagents capable of forming a gas upon reacting with each other in an aqueous environment.

76. The kit of claim 75, wherein one of the two reagents of the effervescent couple is present in the solid composition, whereas the other one is present in the sterile aqueous liquid.