TW200815003A - Treating cystic fibrosis with antibiotics via a swirler delivery - Google Patents

Abstract

The present invention is directed to a method of treating respiratory disorders by delivering an aerosol composition of an antibiotic drug to the lung alveoli.

Description

200815003 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a method of treating a respiratory condition by delivering an antibiotic aerosol formulation to the alveoli. [Prior Art] ‘We are used to delivering drugs to asthma patients using nebulizers and other aerosol devices. However, not all such devices are capable of delivering droplets that are small enough to provide deep lung penetration, which may be beneficial for the delivery of certain drugs, such as antibiotics. Certain aerosol devices are capable of delivering smaller sized droplets required for deep lung penetration. A commercially available example is the S WIRLER® aerosol drug delivery system, which is described in amici-inc.com and U.S. Patent Nos. 5,603,314, 5,630,409, 5,611,332, and 6,230,703. Patents are incorporated herein by reference. As described in more detail in the above patent, the S WIRLER® Aerosol Drug Delivery System is an aerosol inhalation device that provides aerosol aerosol to a patient. The apparatus includes a sprayer having a liquid containing a liquid to be inhaled, a reservoir, a gas inlet for receiving compressed gas, and an aerosol outlet. An important feature of the device is the gas vortex or flow control mode, which creates eddy currents on the aerosol-forming gas, resulting in greater shear forces and smaller particle sizes. The vortex gas creates a vacuum as it exits the outlet and this vacuum draws the liquid away from the reservoir, creating an aerosol. The device is capable of producing aerosol particles having a particle size of less than 1 micron. ZOSYN8 is an injectable antibacterial combination for intravenous administration, which is a semi-synthetic antibiotic, piperacillin sodium 121190.doc 200815003 and (β)-endoprostase inhibitor triterpene bata ( Taz〇bactam sodium) composition. The product is disclosed in U.S. Patent Nos. 4,562,073, 4,477,452, 4,534,977, and 6,207,661. Leuculinine is derived from D(-Ha)-aminobenzyl-penicillin. The chemical name of piperacillin is (2&5 and,6 magic_6-[(and)_2-(4-ethyl-2,3·di-oxy-1-piperazine-carboxamido) Sodium 2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3·2〇]heptane-2-decarboxylate. Chemical formula

CnH^NsNaOj and molecular weight of 539. This product is disclosed in U.S. Patent No. 4,562,073. The chemical structure of sulphate sodium is:

Oxy-3-(1 Η-1,2,3-tris-tris-[3·2·〇]heptane C10H"N4Na〇5S and having a molecular weight of 322.3 in No. 4,958,020. '乂之付生物) Qinghui burning acid (penici_ its chemical name is (2A3 & 5 and) -3_methyl_7_ side ° sit-1 · methyl)-4-thia-1_azabicyclo[3.2.0 Geng

- Oxide. The chemical formula is . This product is revealed in the chemical structure of tribazobactam sodium in the United States.

121190.doc 200815003 TYGACIL® (tigecycline) is a new type of glycosaminoglycan antibacterial agent disclosed in U.S. Patent No. 5,494,903. The chemical name of geigerin is (45,4α&5& and, I2a5>9-1>(t-butylamino)acetamido]-4,7-bis(didecylamino) -154,4&,5,5&,6,11,12^octahydro•3,10,12,12a·tetramyl- ΐ, ιΐ-two-sided oxy (οχο)-]·thick tetrathene ( Naph-thacene). The experimental formula is C29h39N5〇8 and the molecular weight is 585 65. It is a 9-t-butyl-glycine amide derivative of monocycline, which exhibits typical antibiotic activity of tetracycline, but It is more active against drug-resistant efflux and ribosome-protected tetracycline-resistant organisms. geigerin is positive for Gram-positive, Gram-negative, anaerobic and atypical bacteria (atypicals) (including a drug-resistant pathogen) having a broad-spectrum antibacterial activity and being singly singly singly. The product is disclosed in U.S. Patent Nos. 5,494,903, 5,299,900 and 5,284,963. The chemical structure of genomicin:

It is desirable to have these and other antibiotics delivered directly to the lungs of a patient via aerosol to provide an alternative to treating lung disease, such as cystic fibrosis. SUMMARY OF THE INVENTION These and other embodiments are provided by the present invention 121190.doc 200815003 as disclosed and claimed herein. The invention comprises - (iv) a method of treating a respiratory condition comprising administering an antibiotic drug suitable for treating the condition to a mammal in need thereof via a drug delivery system, such as a S WIRLER aerosol drug delivery system, the drug delivery system An aerosol composition of the antibiotic drug is produced wherein the particle size of the antibiotic composition droplets is small enough to provide deep lung penetration. Preferably, at least about 9% (e.g., 95% or more) of the antibiotic droplets in the aerosol are about 1-3 microns or less, more preferably 1; 1 micron or less. Antibiotic aerosols for delivery typically contain antibiotics and diluents. The diluent can be, for example, sterile water for injection, 〇·9% sodium chloride injection, 5% dextrose injection, 5°/. Dextrose and 〇·9% sodium chloride injection, 5% dextrose in lactated Ringers (5%), 5% dextrose-0.45% sodium chloride-〇·ΐ5 % potassium chloride injection or lactated Ringer's solution.

In the practice of the invention, a liquid composition comprising a drug and a diluent is placed in a reservoir of a SWIRLER® aerosol drug delivery system that is in communication with a source of compressed gas that is not reactive with the liquid composition. The device is designed to be subjected to eddy currents to the gas and to produce a fine mist in which the aerosol droplets can be smaller than 丨 microns. 'The latest literature, such as the antibiotics of the present invention, includes anti-infective agents known in the art, which are disclosed by the Medical Economics Company (www.pdr.net) for their agents found in the Physician's Desk Reference (this reference is incorporated herein by reference) ), including but not limited to ZOSYN®, ι & West 121190.doc 200815003 Lin, Erbatan and TYGACIL®. The antibiotic can be administered alone or in combination with other antibiotics. According to the invention, at least one antibiotic is administered as an aerosol medium composition. Other antibiotics can be administered orally, or by intralesional, intraperitoneal, intramuscular or intravenous injection; infusion; liposome-mediated delivery; topical, nasal, transanal, transvaginal, sublingual, transurethral, menstrual Drug delivery by intradermal, intraorbital, transocular or otic delivery. & The compound of the present invention is preferably obtained in a unit dosage form in the supply of the compound of the present invention. Unit dosage forms suitable for S include lozenges, capsules and powders in sachets or pharmaceuticals. Such unit dosage forms may contain from 01 to 300 mg of a compound of the invention, and preferably from 2 to 1 mg. Other preferred unit dosage forms contain from 5 to 5 Torr of the compound of the invention. The effective amount will be known to those skilled in the art; it will also depend on the form of the compound. Those skilled in the art will typically be able to perform an experimental activity test to determine the biological activity of a compound in a biological assay and thereby determine how much dose to administer. [Embodiment] In one embodiment of the invention, a method of delivering an aerosol-containing composition containing an antibiotic via a s WIRLER drug delivery system is provided. The gas/liquid composition may comprise a diluent such as sterile water for injection, 〇·9/. Sodium chloride injection, 5% dextrose injection, 5% dextrose and sodium carbonate injection, 5% dextrose in lactated Ringer's solution, 5% dextrose-0 · 45% sodium chloride _ 〇 15% potassium chloride injection, or lactated Ringer's solution injection. In one embodiment, the antibiotic is suspended in the aerosol medium in a particle size range that meets the microscope's subvisible particle test acceptance criteria, according to 121190.doc -10- 200815003 USP 788', ie no more than 600 particles 225 microns and no more than 6000 particles are 210 microns. In one embodiment, the invention comprises a method of treating a respiratory condition' using a SWIRLER drug delivery system to deliver an aerosol containing an antibiotic compound and at least about 95 <)/ in the aerosol. The particle size of the antibiotic droplets is reduced to about 1-3 microns or less, allowing the antibiotic aerosol to reach the alveoli in the lungs. In another embodiment, at least about 95% of the antibiotic particles are delivered at a particle size of less than 1.1 micron. The method is suitable for treating respiratory conditions such as, but not limited to, cystic fibrosis. The term "about" as used herein is generally meant to be within 2%. It will be appreciated by those skilled in the art that the present invention may be practiced without departing from the spirit or scope of the invention or any embodiment thereof. And equivalent conditions, parameters and similar conditions. For example, piperacillin (2 g_4 ^ Dong dry powder per bottle), tazobactam (0.25 g - 0.50 g / Dong dry powder per bottle), (per 5 bottles of 5 lyophilized powder) or ZOSYN® (2 g-4 g of leuracelin plus 25 〇mg_5 嗤 嗤 嗤 ) ) 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 , , , , , , , , , , , , , , , , , 〇.9% sodium chloride injection, 5% dextrose injection, 5% right sugar and 0.9% sodium chloride injection, 5% dextrose in lactated Ringer's solution / main shot Liquid, 5% dextrose _ 〇 · 45% chlorinated steel _ 〇 5% potassium chloride injection or ritual & salt salt 袼 liquid injection, can use SWIRLER drug delivery system or equivalent aerosol delivery system, Dosing with a particle size ranging from about 1 to about 3 microns and preferably less than about 1.1 microns to ensure delivery of deep lungs 121190.doc 200815003 to the alveolar region of the lungs . Those skilled in the art can readily determine whether the delivery system is capable of providing the aerosol particle size of the present invention. The following examples are provided to illustrate certain embodiments of the invention, but are not to be construed as limiting the scope of the invention. Examples · Tygacil® (Tigerocycline) for deep lung delivery Studies were performed using the commercially available Tygacil® second generation. Sterile water for injection and 0.9% physiological saline were used as a diluent. Tygacil® is a sterile dry powder for intravenous infusion containing 53 mg of tegelcycline active ingredient. Tygacil® additionally contains chylohydrate monohydrate as a diluent/stabilizer and hydrochloric acid and/or sodium hydroxide (if needed) for pH adjustment. This product is supplied in a single-dose, Type I clear small glass vial sealed with a gray butyl rubber stopper and a split-type sweet-skinned cap.

The quantitative composition of Tygacil 16 is described in Table 1 below. Table 1: Quantitative Composition of Tygacil® Reference Standard Function Per Bottle 皇___- 泰格环霉素 a Internal Monograph Active Agent 53 mg Lactose Monohydrate NF/Ph. Eur. b Thinner/Stabilizer 106 mg NF/Ph. Eur. Adjust the pH to adjust the pH value of sodium hydroxide NF/Ph. Eur. Adjust the pH value to adjust the pH value - water for injection ° USP/Ph. Eur. Medium C gas NF/Ph Eur. Cover the right amount to provide a reserved space a. 6% excess is included to compensate for the amount of solution that is not absorbable after preparation, that is, the solution adhered to the inner wall of the vial. b. Internal specifications for bacterial endotoxin testing also apply. c· Removed during lyophilization. Covers the bulk solution and serves as an inert cover in the vial of the charge. _ Before the rehydration, the tegelcycline for injection is an orange powder or cake. 121190.doc -12- 200815003 One (1) bottle of Tygacil® was rehydrated with 100 ml of 0.9% sodium chloride (saline) or sterile water for injection USP. The tegelcycline powder is dissolved in a diluent. A clear yellow to orange solution was obtained. The solution is then transferred to the SWIRLER® unit. Oxygen is supplied to SWIRLER® via an NG tube to atomize the solution. Use an oxygen air pressure regulator to set the air pressure to 15 CFM. The droplet size was measured using a Malvern MXS, S/N 6196. The results show that a high percentage (90%) of the particles are less than 1.1 microns, which is the size required for deep lung delivery. The data is reported in Table 2 below:

Table 2: Particle size distribution of Tygacil® reconstituted with saline or sterile water for injection and administered via SWIRLER® for deep lung delivery

D

D Water ambiguity (%) Test 1 32.7 0.38 0.58 0.93 Test 2 32.7 0.41 0.61 0.99 Test 3 36.7 0.37 0.56 0.88 〇.9% NaCl

Test Dance 1 Test 2 Test 3 0.9% NaCl + TYG* Test 1 i Test 2 Test 3 28.1 31 33.9 27.8 16.6 14.9 0.42 0.62 1.02 0.4 0.6 0.98 0.4 0.41 0.39 0.38 0.6 0.61 0.59 0.58 0.98 0.96 0.94 〇.9% NaCl + TYG ** Test 1 Test 2 28 25.2 0.45 0.44 0.65 0.64 1.11 1.1 Test 3 30.4 0.44 0.65 1.08 ^^ Test 1 32.9 0.42 0.62 1.01 3 Test 2 30.6 1 0.41 0.61 0.99 Test 3 33.5 0.41 0.61 1 121190.doc • 13 - 200815003 * Dissolve 50 mg (l 槪) of Tygacil® with 100 ml of 0.9% sodium chloride (normal saline) ** Dissolve 100 mg (2 bottles) of Tygacil 8 with 100 ml of 0.9% sodium chloride (normal saline)

_ Dissolve 5 bottles with 100 ml sterile water for injection (usp)) Tygacil® cooked

For example, the skilled person in the art understands that the invention is not limited to the embodiments described and described herein, and also covers all of the subject matter within the scope of the appended claims:

121190.doc -14·

Claims (1)

200815003 X. Patent application scope: 1. A drug delivery system for treating respiratory diseases, comprising S WIRLER drug delivery system, comprising antibiotic drugs Z〇SYN, piperacillin, Tazobactam Or TYGACIL, and a liquid aerosol composition for producing the antibiotic drug, wherein at least about 90% of the antibiotic droplets in the aerosol have a particle size of about 1 to 3 microns or less. 2. The drug delivery system of claim 1, wherein the aerosol composition of at least about 95 Å/〇 has a particle size of 1.3 micron or less. 3. The drug delivery system of claim 1 or 2, wherein at least about 90% of the antibiotic droplets in the aerosol have a particle size of about 1 · i microns or less. 4. The drug delivery system of claim 1 or 2, wherein at least about 95% of the antibiotic droplets in the aerosol have a particle size of about hl microns or less. 5. The drug delivery system of claim 1 or 2, wherein the aerosol composition comprises an antibiotic and a diluent. The drug delivery system of claim 5, wherein the diluent comprises sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium sulphate injection, 5% Injection of dextrose in lactated Ringers, 5% dextrose-〇·45% sodium chloride _ 〇·15% potassium chloride injection, or lactated Ringer's solution Injection. The drug delivery system of claim 1 or 2, wherein the respiratory condition is cystic fibrosis. 8. The drug delivery according to claim 1 or 2, wherein the antibiotic is administered alone or in combination with other antibiotics. 121190.doc 200815003 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: (none) 121190.doc