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WO2000019991A1 - Chimiotherapie par inhalation pour la prevention et le traitement des tumeurs metastatiques du poumon - Google Patents

Chimiotherapie par inhalation pour la prevention et le traitement des tumeurs metastatiques du poumon Download PDF

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Publication number
WO2000019991A1
WO2000019991A1 PCT/US1999/022845 US9922845W WO0019991A1 WO 2000019991 A1 WO2000019991 A1 WO 2000019991A1 US 9922845 W US9922845 W US 9922845W WO 0019991 A1 WO0019991 A1 WO 0019991A1
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drug
drugs
inhalation
dose
pulmonary
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PCT/US1999/022845
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English (en)
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Anthony R. Imondi
Michael E. Placke
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Battelle Memorial Institute
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Priority to AU12001/00A priority Critical patent/AU1200100A/en
Priority to CA002346029A priority patent/CA2346029A1/fr
Publication of WO2000019991A1 publication Critical patent/WO2000019991A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention deals with methods useful for preventing metastasis and treating metastatic neoplasms, particularly neoplasms that metastasize to the respiratory tract (e.g. hemangiosarcoma), by treating the primary tumor by known methods and using in addition methods for the pulmonary administration of one or more antineoplastic drugs and concurrent systemic administration of one or more antineoplastic drugs.
  • Cancer is one of the leading causes of death worldwide. Lung cancer in particular, is among the top 3 most prevalent cancers and has a very poor survival rate (about 13% five-year survival rate). Despite the availability of many cancer drugs it has been difficult and, in the case of some cancer types, almost impossible to improve cure rates or survival. There are many reasons for this lack of success but one reason is the inability to deliver adequate amounts of the drugs to the tumor without causing debilitating and life- threatening toxicities in the patient. Indeed, most chemotherapeutic drugs used to treat cancer are highly toxic to both normal and tumor tissues. It is customary in the treatment of cancer to administer the drugs by the intravenous route, which exposes the entire body to the drug. Doses are selected that destroy tumor cells, but these doses also destroy normal cells.
  • the patient usually experiences severe toxic side effects. For example, severe myelosuppression may result which compromises the ability of the patient to resist infection and allows spread of the tumor.
  • severe myelosuppression may result which compromises the ability of the patient to resist infection and allows spread of the tumor.
  • There are other life-threatening effects such as hepatotoxicity, renal toxicity, pulmonary toxicity, cardiotoxicity, neurotoxicity, and gastrointestinal toxicity caused by anticancer drugs.
  • the anticancer drugs also cause other effects such as alopecia, stomatitis, and cystitis that may not be life threatening, but are serious enough to affect a patient's quality of life.
  • these toxicities are not associated to the same extent with all anticancer drugs but are all due to systemic delivery of the drug.
  • anthracyclines such as doxorubicin, epirubicin and idarubicin are known to cause severe cardiotoxicity.
  • Doxorubicin additionally, is known to cause severe progressive necrosis of tissues when extravasated.
  • Cisplatin therapy is known to cause renal toxicity; vincristine causes neurotoxicity, bleomycin and mitomycin cause pulmonary toxicity, cyclophosphamide causes cystitis; and 5-fluorouracil causes cerebral disjunction (see Cancer Chemotherapy: Principles and Practice, BA Shabner and J.M. Collings, eds. J.B. Lippincott Co., Philadelphia, 1990).
  • the differences in mechanisms of action and pharmacokinetic properties determine, in part, the efficacy of the various anticancer drugs against different tumor types, which exhibit various biological behaviors.
  • anticancer drugs are instilled directly into the bladder through the urethra, allowed to remain in contact with the tumor for a period of time and then voided.
  • Other examples of regional therapy include the delivery of anticancer drugs into the peritoneal cavity to treat cancer that has developed in or metastasized to this location.
  • Other methods of targeting anticancer drugs involve the attachment of the drugs to antibodies that seek out and deliver the drug directly to the cancer cells.
  • the drugs were given to healthy animals and included: thiotepa (rats), Toyomycin (chromomycin A3) (rats,), endoxan (cyclophosphamide) (rats and rabbits), 5- fiuorourcil (rats and rabbits), mitomycin-C (rats, rabbits, and dogs).
  • the results of these tests showed that: 5-FU and cyclophosphamide resulted in only mild inflammation; thiotepa produced bronchial obstruction; chromomycin A3 and mitomycin-C produced the most severe results.
  • Toxic effects of mitomycin-C and chromomycin A3 were studied in rabbits and dogs.
  • Tatsumura et al Jap. J.
  • 5-FU is considered to be one of the least toxic anticancer drugs when applied directly to tissue. Indeed, 5-FU is used as a topical drug for the treatment of actinic keratosis for which it is applied liberally, twice daily, to lesions on the face. This therapy may continue for up to four weeks. Also, because 5-FU is poorly absorbed from the gastrointestinal tract, there is little concern about the amount of drug that may be inadvertently swallowed and gain access to the blood stream from the gut. It is well known that a large percentage of aerosolized drug intended for the lung is swallowed.
  • Liposome encapsulated and free Ara-C were instilled intratracheally to the rats as a bolus.
  • the encapsulated Ara-C persisted for a long time in the lung while the free Ara-C which is not highly protein bound was rapidly cleared from the lung.
  • the free Ara-C rapidly diffused across the lung mucosa and entered the systemic circulation.
  • liposome encapsulation of drugs may be a way to produce local pharmacologic effect within the lung without producing adverse side effects in other tissues.
  • bolus administration results in multifocal concentrated pockets of drug. See the articles by H.N.
  • the cisplatin exposed inhalation group were reported to have statistically smaller lung tumor sizes and survived longer than the untreated control group. See A. Kinoshita, "Investigation of Cisplatin Inhalation Chemotherapy Effects on Mice after Air Passage Implantation of FM3A Cells", J. Jap. Soc. Cancer Ther. 28(4): pp. 705-715 (1993).
  • compositions where a pharmaceutically active agent is enclosed within a polymeric shell for administration to a patient.
  • routes of administration listed as possible for the compositions of the invention is inhalational.
  • pharmaceutically active agents potentially useful in the invention are anticancer agents such as paclitaxel and doxorubicin. No tests using the inhalational rout of administration appear to have been made.
  • antineoplastic drugs have been administered to animals and to humans, for treatment of tumors in the lungs and respiratory system, the differences in the mechanism of action, and toxicity profiles among the broad classes of anticancer drugs, and the heretofore known characterizations have made it impossible to predict whether a particular anticancer drug will be efficacious or toxic based upon previous inhalation results with a different drug of a different type. Further, previous reports used very imprecise means of delivering drugs and were not consistent in delivering measured doses of drugs in an evenly distributed manner to the entire respiratory tract.
  • the present invention provides means for predicting and selecting drugs including the highly toxic chemotherapeutic compounds, amenable for inhalation therapy of neoplastic disease and methods for actually distributing specific measured doses to pre-selected regions of the respiratory tract.
  • anticancer cytotoxic drugs of multiple classes such as anthracyclines (doxorubicin), antimicrotubule agents such as the vinca alkaloids (vincristine), and taxanes such as paclitaxel can be given directly by inhalation without causing severe toxicity to the lung or other body organs.
  • doxorubicin anthracyclines
  • antimicrotubule agents such as the vinca alkaloids (vincristine)
  • taxanes such as paclitaxel
  • the present invention provides an effective way to administer chemotherapeutic agents, including highly toxic agents such as doxorubicin, while minimizing the major side effects described above.
  • the present invention discloses methods for treating a patient for a neoplasm and for preventing pulmonary metastasis from the neoplasm to the lung including the steps of (a) treating the patient for the primary neoplasm wherein the treatment is selected from the group consisting of partial or complete surgical excision, radiation therapy, local-regional chemotherapy, immunotherapy, gene therapy and combinations thereof;
  • administering an antineoplastic drug to the patient by inhalation typically involves administering an effective amount of one or more antineoplastic drugs to the patient by inhalation; and administering an effective amount of one or more of the same or different antineoplastic drug to the patient systemically.
  • the patient is a mammal such as a human.
  • the method includes drugs wherein when 0.2 ml of at least one of the drugs is injected intradermally to rats, at the clinical concentration for parenteral use in humans: a lesion results which is greater than 20 mm 2 in area fourteen days after the intradermal injection; and at least 50% of the tested rats have these lesions.
  • Figure 1 shows the plasma drug concentration time profile for dog #101 having doxorubicin administered intravenously (IV) (circles) and by the pulmonary inhalation route (IH) (squares).
  • IV intravenously
  • IH pulmonary inhalation route
  • the vertical Y scale is the concentration of drug in the circulatory system in ng/ml and the horizontal X scale is time after treatment in hours.
  • Figure 2 shows the plasma drug concentration time profile for dog #102 having doxorubicin administered intravenously (IV) (circles) and by the pulmonary inhalation route (IH) (squares).
  • IV intravenously
  • IH pulmonary inhalation route
  • the vertical Y scale is the concentration of drug in the circulatory system in ng/ml and the horizontal X scale is time after treatment in hours.
  • Figure 3 shows the plasma drug concentration time profile for dog #103 having doxorubicin administered intravenously (IV) (circles) and by the pulmonary inhalation route (IH) (squares).
  • IV intravenously
  • IH pulmonary inhalation route
  • the vertical Y scale is the concentration of drug in the circulatory system in ng/ml and the horizontal X scale is time after treatment in hours.
  • Figure 4 shows a schematic of the pulmonary delivery apparatus arrangement that was used to administer drug to dogs by inhalation for Example 3.
  • Figure 5 shows a schematic of the pulmonary delivery apparatus arrangement that was used to administer high doses and multiple doses of drug to dogs by inhalation for Example 4.
  • Figure 6 shows a schematic drawing of details of a mask useful for administering drugs by inhalation to a mammal such as a dog.
  • Figure 7 shows a schematic drawing of a portable device for administration of anticancer drugs according to the invention.
  • Figure 8 is a graph showing data derived from dogs treated for hemangiosarcoma, where the Vertical Scale shows the percent of dogs that are alive (Y-axis) and the horizontal scale (X-axis) shows the number of days survival.
  • the inventors have discovered that highly toxic, vesicant and previously unknown nonvesicant antineoplastic drugs can be effectively delivered to a patient in need of treatment for neoplasms or cancers by inhalation.
  • This route is particularly effective for treatment of neoplasms or cancers of the pulmonary system because the highly toxic drugs are delivered directly to the site where they are needed, providing regional doses much higher than can be achieved by conventional IV delivery.
  • the respiratory tract includes the oral and nasal-pharyngeal, tracheo-bronchial, and pulmonary regions.
  • the pulmonary region is defined to include the upper and lower bronchi, bronchioles, terminal bronchioles, respiratory bronchioles, and alveoli.
  • vesicants as used herein include chemotherapeutic agents that are toxic and typically cause long lasting damage to surrounding tissue if the drug is extravasated. If inadvertently delivered outside of a vein, a vesicant has the potential to cause pain, cellular damage including cellulitis, tissue destruction (necrosis) with the formation of a long lasting sore or ulcer and sloughing of tissues that may be extensive and require skin grafting. In extreme cases extravasation of vesicants such as doxorubicin has required surgical excision of the affected area or amputation of the affected limb.
  • antineoplastic chemotherapeutic agents that are generally accepted vesicants include alkylating agents such as mechlorethamine, dactinomycin, mithramycin; topoisomerase II inhibitors such as bisantrene, doxorubicin (adriamycin), daunorubicin, dactinomycin, amsacrine, epirubicin, daunorubicin, and idarubicin; tubulin inhibitors such as vincristine, vinblastine, and vindesine; and estramustine.
  • alkylating agents such as mechlorethamine, dactinomycin, mithramycin
  • topoisomerase II inhibitors such as bisantrene, doxorubicin (adriamycin), daunorubicin, dactinomycin, amsacrine, epirubicin, daunorubicin, and idarubicin
  • tubulin inhibitors such as vincristine
  • vesicants as more narrowly used herein include drugs that produce a lesion in rats, where the average lesion size is greater than about 20 mm 2 in area, fourteen days after an intradermal injection of 0.2 ml of the drug, and where 50% or more of the animals have this size of lesion.
  • the drug concentration for the intradermal injection is the clinical concentration recommended by the manufacturer for use in humans, the dose recommended in the Physicians Desk Reference, 1997 (or a more current version of this reference), or another drug manual for health specialists. If there is no recommendation by the manufacturer (for example for because the drug is new) and there is no recommendation in the Physicians Desk Reference or similar drug manual for health specialists then other current medical literature may be used. If more than one clinical concentration is recommended, the highest recommended clinical concentration is used.
  • Lesion as used herein means an open sore or ulcer or sloughing off of skin with exposure of underlying tissue.
  • 0.2 ml of a highly toxic anticancer drug (vesicant) at a dose recommended for humans (as discussed above) is administered intradermally to rats at a concentration that causes the above mentioned lesion size for a more extended period of time. That is, the lesions remain above about 10 mm 2 up to at least 30 days in at least 50% or more of the animals.
  • Nonvesicants typically are also irritating and can cause pain, but do not usually result in long lasting sores or ulcers or sloughing off of tissues except in exceptional cases.
  • alkylating agents such as cyclophosphamide, bleomycin (blenoxane), carmustine, and dacarbazine
  • DNA crosslinking agents such as thiotepa, cisplatin, melphalan (L-PAM)
  • antimetabolites such as cytarabine, fluorouracil (5-FU), methotrexate (MTX), and mercaptopurine (6 MP); topoisomerase II inhibitors such as mitoxantrone; epipodophyllotoxins such as etoposide (VP-16) and teniposide (VM-26); hormonal agents such as estrogens, glucocorticosteroids, progestins, and antiestrogens; and miscellaneous agents such as asparaginase, and streptozocin.
  • Table 1 A listing of materials usually accepted to be vesicants or nonvesicants is provided below as Table 1- Vesicant/Nonvesicant Drug Activity. Table 1
  • Typical embodiments of the invention use highly toxic antineoplastic drugs that have similar or greater vesicating activity than those that have been tested in animals by inhalation to date.
  • One embodiment typically uses severely vesicating toxic antineoplastic drugs having higher vesicating activity than those represented by 5-FU, ⁇ -cytosine arabinoside (Ara-C, cytarabine), mitomycin C, and cisplatin.
  • a highly toxic drug represented by the class anthracyclines of which doxorubicin is among the most toxic
  • vesicants other than doxorubicin can be given to patients by inhalation.
  • highly toxic drugs represented by the classes vinca alkaloids, and taxanes, having similar high toxicities have been administered by inhalation to a patient in need of treatment for neoplasms.
  • certain antineoplastic drugs that are nonvesicants can be administered by inhalation to a patient in need of treatment for neoplasms.
  • formulations and methods for applying the aforementioned highly toxic drugs to a patient in need of treatment for pulmonary neoplasms by inhalation are disclosed.
  • This example illustrates and confirms toxicity and vesicant/nonvesicant activity of several antineoplastic drugs.
  • the vesicant activities of thirteen anticancer drugs were investigated (see the listing in Table 2 below).
  • Doxorubicin has traditionally been considered a vesicant (see Table 1).
  • Paclitaxel has previously been considered a nonvesicant, but recent literature has advocated its classification as a vesicant. Some of the remaining drugs are traditionally considered to be vesicants and others nonvesicants (Table 1). Day fourteen after injection was chosen as the time for comparison for vesicant activity, because lesions caused by nonvesicants should have been significantly reduced while lesions caused by vesicants should still be large. Sterile saline solution (0.9%) for injection USP, pH 4.5-7.0, or sterile water for injection, as appropriate, was used to reconstitute the drugs.
  • the drugs used for the vesicant activity tests are identified as follows: doxorubicin (Adriamycin PFS), a red liquid in glass vials, no formulation was necessary; cisplatin (Platinol-AQTM), a liquid in glass vials, no formulation was necessary; Paclitaxel (TaxolTM), a liquid in glass vials, formulated with saline solution; fluorouracil, a clear yellow liquid in glass vials, no formulation was necessary; cytarabine (Cytosar-UTM), a white powder in glass vials, formulated with water; 9-aminocamptothecin (9-AC colloidal suspension), a yellow powder in glass vials, formulated with water; cyclophosphamide (CytoxanTM), a yellow powder in glass vials, formulated with a saline/water mixture; carboplatin (ParaplatinTM), a white powder in injectable vials, formulated
  • the tests for vesicant activity were conducted using Sprague Dawley rats (7-8 weeks old having 150-200 g of body weight. Each received a single intradermal injection of the test drug at the recommended clinical concentration (listed below in Table 2) in the right dorsum. Approximately 24 hours prior to administration, the hair was removed from the dorsum using clippers and a depilatory agent. Each 0.2 ml injection was given with a 1 ml syringe and 27 gauge needle. All drug solutions were either isotonic or slightly hypertonic. Table 2
  • Table 3 below is a tabulation of the resultant lesion sizes that developed from intradermal injections of the above drugs. Lesion sizes were measured as more fully discussed below.
  • doxorubicin 3/7
  • paclitaxel 7/7
  • fluorouracil 7/7
  • etoposide 7/7
  • bleomycin 7/7
  • vincristine 2/7
  • vinorelbine 7/7
  • mitomycin-C mutamycin
  • Dermal lesions at the site of injection were determined to be the best and most objective measure and predictor of vesicant activity for a drug. Lesion size was quantitated by micrometer measurements of the two largest perpendicular diameters and the two values multiplied to yield a lesion area in mm 2 . Lesions were regularly evaluated and scored as shown in Table 3.
  • a vesicant as determined by the methods used herein is defined as causing a lesion of at least about 20 mm 2 , in at least one half of the animals, two weeks after injection (day 15 in Table 3).
  • Table 3 shows that doxorubicin, paclitaxel, carboplatin, vincristine, vinorelbine, and mitomycin-C fulfill these criteria. Cisplatin, etoposide, bleomycin, cytarabine, cyclophosphamide, fluorouracil, and 9-aminocamptothecin are thus categorized as non-vesicants.
  • a moderate vesicant as determined by the methods used herein is defined as causing a lesion of at least about 20 mm 2 , in at least one half of the animals, two weeks after injection (day 15 in Table 3), but less than half of the animals will have lesions greater than about 10 mm 2 30 days after injection (day 31 in Table 3).
  • the data from Table 3 shows that paclitaxel, carboplatin, and mitomycin-C fulfill these criteria. Of these, mitomycin-C has been determined to exhibit substantial pulmonary toxicity.
  • a severe vesicant as determined by the methods used herein is defined as causing a lesion of at least about 20 mm 2 , in at least one-half of the animals, two weeks after injection (day 15 in Table 3), and at least one-half of the animals will still have lesions greater than about 10 mm 2 , 30 days after injection (day 31 in Table 3).
  • Table 3 shows that doxorubicin, vincristine, and vinorelbine satisfy these criteria.
  • moderate to severe vesicants can be used for inhalation therapy of cancer as revealed in the discussion and examples below.
  • other highly toxic drugs although not having the severity of reaction of moderate to severe vesicants have also been found to be useful in the treatment of cancer by inhalation as further discussed below.
  • Antineoplastic drugs that are highly toxic and useful in an embodiment of the present invention include the anthracyclines (e.g. doxorubicin, epirubicin, idarubicin, methoxy-morpholinodoxorubicin, daunorubicin, and the like); vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and the like); alkylating agents (e.g. mechlorethamine and the like); carboplatin; nitrogen mustards (e.g. melphalan and the like), topoisomerase I inhibitors (e.g.
  • anthracyclines e.g. doxorubicin, epirubicin, idarubicin, methoxy-morpholinodoxorubicin, daunorubicin, and the like
  • vinca alkaloids e.g. vincristine, vinblastine, vindesine, and the like
  • alkylating agents e.g. mechlore
  • antineoplastic drugs by the pulmonary route as a means to provide systemic treatment of distant tumors.
  • the inventors have shown that for selected drugs inhalation can be used as a noninvasive route of delivery without causing significant toxicity to the respiratory tract. This is in contrast with the prior art that used inhalation for treatment of disease in the respiratory system.
  • patient includes a mammal including, but not limited to, mice, rats, cats, horses, dogs, cattle, sheep, apes, monkeys, goats, camels, other domesticated animals, and of course humans.
  • Administration by inhalation includes the respiratory administration of drugs as either liquid aerosols or powdered aerosols suspended in a gas such as air or other nonreactive carrier gas that is inhaled by a patient.
  • Non-encapsulated drug as used herein means that the antineoplastic drug is not enclosed within a liposome, or within a polymeric matrix, or within an enclosing shell.
  • encapsulated drug is used herein the term means that the antineoplastic drug is enclosed within a liposome, within a polymeric matrix, or within an enclosing shell.
  • the antineoplastic drug may be coupled to various molecules yet is still not enclosed in a liposome, matrix or shell as further discussed below.
  • the antineoplastic drugs disclosed herein may be coupled with other molecules through ester bonds. Enzymes present in the respiratory system later cleave the ester bonds.
  • One purpose of coupling the antineoplastic drugs through an ester bond is to increase the residence time of the antineoplastic drug in the pulmonary system. Increased residence time is achieved by: first, an increase in molecular weight due to the attached molecule; second, by appropriate choice of a coupled molecule; third, other factors such as for example charge, solubility, shape, particle size of the delivered aerosol, and protein binding can be modified and used to alter the diffusion of the drug.
  • Molecules useful for esterification with the drug include alpha-hydroxy acids and oligomers thereof, vitamins such as vitamins A, C, E and retinoic acid, other retinoids, ceramides, saturated or unsaturated fatty acids such as linoleic acid and glycerin.
  • Preferred molecules for esterification are those naturally present in the area of deposition of the active drug in the respiratory tract.
  • doxorubicin was used in a series of tests. Doxorubicin was chosen as an initial test agent since it is one of most cytotoxic and potent vesicants of all anti-neoplastic agents considered in the broad embodiment (pulmonary delivery of anti-neoplastic drugs) of the present invention. Based on positive outcome of these proof of concept studies, anticancer drugs from other major classes were simultaneously tested. Results consistently showed that using the approach and methods described in this invention the drug could be safely and effectively delivered by inhalation. In Examples 2 and 3 below, doxorubicin was administered to three dogs (beagles) by both the pulmonary and intravenous route of administration. The dogs were given a clinically effective dosage of the drug and the amount of the drug appearing in the blood system was measured.
  • An anthracycline antineoplastic drug a salt of doxorubicin, doxorubicin HCI, available from Farmitalia Carlo Erba (now Pharmacia & Upjohn), Milan, Italy, was used in some of the examples herein.
  • the liquid formulation that was administered to the dogs by inhalation of an aerosol was obtained by mixing the doxorubicin hydrochloride with a mixture of ethanol/water at a doxorubicin concentration of approximately 15 - 25 mg/ml. Typically solutions of 5 - 75% ethanol are preferred. Water/ethanol ratios may be adjusted to select the desired concentration of doxorubicin and the desired particle size of the aerosol.
  • the dogs (designated dog 101, 102, and 103) had body weights of 10.66, 10.24, and 10.02 kg respectively .
  • m 2 used alone with reference to dose refers to square meters in terms of the body surface area of a treated animal or patient, at other times it is qualified in terms of lung surface area.
  • the dogs were given a slow IV infusion treatment of the anthracycline drug doxorubicin HCI at the recommended initial clinical dose (for dogs) of 20 mg/m 2 or 1 mg/kg of body weight.
  • a 1 mg/ml drug solution was administered at a rate of 2.0 ml/kg/hr for 30 minutes.
  • the 30-minute infusion interval simulated the time/dose exposure relationship of the inhalation group in Example 3 below.
  • a series of blood samples were taken to characterize the IV pharmacokinetics at predose, 2, 5, 10, 30, 60, 90 minutes and 2, 4, 6, 12, 18, and 36 hours post dosing. Additional blood samples were collected for clinical pathology evaluations on days 3 and 7 of the IV treatment. Changes in blood chemistry and hematology were as expected with administration of doxorubicin HCI at these doses.
  • Example 3 The three dogs used in Example 2 were allowed a one-week washout period before being subjected to exposure to the anthracycline drug doxorubicin HCI by inhalation. The dogs were acclimated to wearing masks for administration of the aerosol prior to treatment. The dogs were exposed to an aerosol concentration of drug sufficient to deposit a total dose of about 10 mg (1 mg/kg). Based on aerosol dosimetry models, approximately one half of this dose was deposited within the respiratory tract. The total dose was about equal to the dosage administered by IV infusion. The dose was calculated using the following equation:
  • Dose ⁇ Drug Cone, (mg/liter) x Mean minute Vol. (liter/min) x Exposure Duration (min) x Total Deposition Fraction (%) ⁇ ⁇ Body Weight (kg)
  • Pulmonary function measurements (respiratory rate, tidal volume, and minute volume (calculated)) were monitored during a 30 minute inhalation exposure session. These data provided an estimate of each animal's inspired volume during exposure, and were used to calculate the mass of drug deposited in the respiratory tract. A series of blood samples were collected at the end of the exposure to characterize the pharmacokinetics. Clinical pathology evaluations were conducted on the third day. All three dogs were necropsied on the third day. Referring now to Figure 4, the drug formulation was administered to the dogs of Example 3 with drug exposure system 400. The drug was aerosolized with two Pari LC Jet PlusTM nebulizers 401 .
  • the nebulizer was filled with a solution of 15 mg doxorubicin per mi of 50%water/50% ethanol.
  • the output of each nebulizer 401 was continuous and set to provide the required concentration of aerosol in attached plenum 405.
  • the nebulizers 401 were attached directly to plenum 405 that had a volume of approximately 90 liters .
  • Plenum 405 was connected by four tubes 407 to four venturi 40?, respectively, and subsequently connected to four Y-fittings 413 by additional tubing 411. Typical venturi were used to measure the inhaled volume of drug formulation.
  • each of the Y-fittings 411 interfaced with a dog breathing mask 415 while the other end of Y-fitting 411 was connected to tubing 417 leading to an exhaust pump 419.
  • three dogs 418 were fitted with three of the breathing masks 415.
  • a collection filter 421 was placed in the remaining mask 415.
  • a vacuum pump 423 that drew 1 liter per minute of air for 3 minutes was used in the place of a dog to draw aerosol in order to monitor and measure the amount of drug administered. The vacuum pump was activated four times during the 30-minute administration of drug to the dogs and the amount of drug trapped by the filter set forth in Table 5 below.
  • a flow of air was supplied to each of the nebulizers 401 from a supply of air 425 via lines 427. Additional air for providing a bias flow of air through the system and for the breathing requirements of the dogs was provided from air supply 425 by supply lines 429 connected to one way valves 431. The one way valves 431 were connected to the upper portion of the nebulizers 401. This additional supply of air provided a continuous flow of air through the system 400 from the air supply 425 to the exhaust pump 417. Alternatively one could eliminate the extra supply of air from supply lines 429 to one way valves 431 and let ambient room air enter the one way valves from the suction action of the nebulizers 401.
  • a Hepa filter 441 mounted to the top of plenum 405 allowed room air to flow in and out of plenum 405 and assured that there was always ambient pressure in the plenum. There was a continuous flow of air containing the aerosol past the masks of the dogs and the dogs were able to breathe air containing the aerosol on demand.
  • An inner tube 621 located within dog breathing mask 415 extended into the mouth of the dogs and was provided with an extension 633 at its lower portion that served to depress the tongue of the dogs to provide an open airway for breathing. See the discussion of Figure 6 below.
  • Each of the four venturi 409 were connected by line 441 to a pressure transducer 443 (the one shown is typical for the four venturi) that was used to measure pressure differences across the venturi.
  • the pressure transducers 443 were connected by line 445 to an analog amplifier 447 to increase the output signal and prepare the signal sent via line 449 to computer system 451.
  • Computer system 451 is a desk model PC of typical design in the industry and can be used in conjunction with a BUXCO or PO-NE-MAH software program to calculate the uptake of air containing aerosol and thus the drug dosage by each of the dogs.
  • Table 4 summarizes the exposure data for doxorubicin administration to dogs from Example 3.
  • the total mass for each dog was determined.
  • the total inhaled volume of air for the 30 minute drug administration was measured in liters.
  • the aerosol concentration in mg of drug/liter of air (mg/1) was determined from calibration tests done earlier.
  • a total deposition fraction of 60% was calculated (As calculated 30% for the inhaled dose was deposited in the conducting upper airways and peripheral lung while and additional 30% was deposited in the oral-pharyngeal region) based on the measured doxorubicin aerosol particle size and the published literature (see references cited above).
  • Filter data obtained from analysis of drug deposited on a filter 421 placed in a fourth mask 415 are shown in Table 5 for four different measurements .
  • the drug mass collected on the filter was corrected for the chlorine portion of the doxorubicin salt.
  • the doxorubicin concentration in the three liters of air drawn into each mask was determined in mg/1. The four figures were averaged to obtain a mean doxorubicin aerosol concentration of 0.218 mg/1.
  • Table 6 shows data and calculations that verify the figures of Table 4.
  • the dog weight and breath volumes measured for Table 4 are used.
  • the mean doxorubicin concentration that was obtained from the filter data shown in Table 5 was used to calculate doxorubicin concentrations.
  • Making calculations with the data as in Table 4, the inhaled dose for each dog was calculated.
  • the inhaled dose was reduced by 40% as before to obtain the total dose deposited, and reduced by 50% again to obtain the total deposited pulmonary dose.
  • the pulmonary doses obtained by this method of 0.47, 0.56, and 0.53 mg/kg for dogs 101, 102, and 103 respectively compare well with the earlier calculated figures in Table 4.
  • Figures 1, 2 and 3 show examples of the type of results achieved when cytotoxic anticancer drugs were given by inhalation.
  • High efficiency nebulization systems as shown in Figures 4 and 5 were used to deliver a large percentage of aerosolized drug to the pulmonary region of the respiratory tract. Doses equal to or greater than those that cause toxicity when given IV, were only moderately absorbed into the blood following pulmonary delivery and caused little to no direct or systemic toxicity after a single exposure at this dose.
  • the pulmonary route administered doxorubicin achieved a consistently lower level of doxorubicin in systemic blood, with peak blood levels being over an order of magnitude lower following inhalation exposure.
  • the initial concentration of doxorubicin at 2 minutes was about 1.5 orders of magnitude larger when administered IV than by the pulmonary route.
  • the systemic doxorubicin level was about six times higher for the IV administered drug. This suggests that free doxorubicin remained in the lung for an extended period of time and slowly passed through the mucosa into systemic circulation. This reduces the systemic toxic effects of the drug and allows its concentration in the lung for more effective treatment of respiratory tract associated neoplasms while reducing overall systemic toxic effects. It is believed that the toxic effects of doxorubicin to tissues outside the lung are as a result of the aforementioned high levels of systemic drug concentration following IV treatment.
  • doxorubicin administered by the pulmonary route did not produce the severe toxic effects on the respiratory tract (including the oral and nasal-pharyngeal, tracheo-bronchial, and pulmonary regions).
  • doxorubicin belongs to the anthracycline class of drugs that are typically very toxic.
  • doxorubicin is one of the most toxic drugs in the class, yet when the dogs in the test were necropsied, no damage to the respiratory tract was observed. It is surprising that the doxorubicin was not toxic to the lung when given by inhalation at clinically relevant doses such as 20 to 60 mg/m 2 .
  • doxorubicin is well known to generate the production of free radicals (Myers et al, 1977) which are notorious for causing pulmonary toxicity (Knight, 1995). It is this property, in fact, which is held responsible for the cardiotoxicity caused by doxorubicin given by the intravenous route (Myers et al, 1977).
  • antineoplastic drugs administered in non- encapsulated form by the pulmonary route be absorbed into and remain in the tumor tissue for an extended period of time and diffuse across the lung mucosa in a relatively slow manner.
  • solubility, charge and shape have an influence, slow diffusion is obtained by drugs having higher molecular weights while faster diffusion is obtained by those having relatively lower molecular weights.
  • drugs such as doxorubicin having a molecular weight of 543.5
  • drugs having somewhat lower molecular weights such as 9- aminocamptothecin, while diffusing more slowly are still included within the invention. It has been demonstrated that significantly higher tissue concentrations can be achieved in the lung by pulmonary delivery compared to conventional parenteral or oral administration. Further, systemic coverage of mierometasteses can be provided under these conditions, with the benefit of significantly greater doses of drug delivered to the respiratory tract tumor sites and controlled systemic exposure.
  • drugs having a molecular weight above 350 are used.
  • mitomycin-C MW of about 3344
  • molecular weight is not the sole determinant controlling diffusion through the lung it is one of the important factors for selecting compounds useful in the present invention. This lower molecular weight limit is about 64% that of doxorubicin. This will help assure that the limited systemic availability of the drug discussed above is maintained.
  • the molecular weight of the drugs administered is above 400, 450, and 500 respectively.
  • protein binding of the antineoplastic agents to be delivered by pulmonary administration should also be considered with respect to diffusion through the lung.
  • 5-FU and Ara-C in addition to having low molecular weights also have relatively low protein binding affinity of 7% and 13% respectively. That is, when placed into a protein-containing solution, only 7% and 13% of these drugs bind to the protein while the remainder is free in solution.
  • cisplatin does not bind to tissues, rather at a later stage it is the platinum in the cisplatin that binds to tissues, thus allowing cisplatin to enter systemic circulation as further discussed below.
  • doxorubicin, vincristine, vinblastine, paclitaxel, etoposide, and 9- amino-camptothecin have rates of protein binding above 50%.
  • protein-binding affinity above 25% is preferred, more preferred is binding above 50%, with protein binding above 75% being most preferred when lung retention is the objective.
  • the diffusion characteristics of the particular drug formulation through the pulmonary tissues are chosen to obtain an efficacious concentration and an efficacious residence time in the tissue to be treated. Doses may be escalated or reduced or given more or less frequently to achieve selected blood levels. Additionally the timing of administration and amount of the formulation is preferably controlled to optimize the therapeutic effects of the administered formulation on the tissue to be treated and/or titrate to a specific blood level. Diffusion through the pulmonary tissues can additionally be modified by various excipients that can be added to the formulation to slow or accelerate the absorption of drugs into the pulmonary tissues.
  • the drug may be combined with surfactants such as the phospholipids, dimyristoylphosphatidyl choline, and dimyristoylphosphatidyl glycerol.
  • surfactants such as the phospholipids, dimyristoylphosphatidyl choline, and dimyristoylphosphatidyl glycerol.
  • the drugs may also be used in conjunction with bronchodilators that can relax the bronchial airways and allow easier entry of the antineoplastic drug to the lung.
  • Albuterol is an example of the latter with many others known in the art.
  • the drug may complexed with biocompatible polymers, micelle forming structures or cyclodextrins
  • Particle size for the aerosolized drug used in the present examples was measured at about 2.0-2.5 ⁇ m with a geometric standard deviation (GSD) of about 1.9-2.0.
  • the particles should have a particle size of from about 1.0-5.0 ⁇ m with a GSD less than about 2.0 for deposition within the central and peripheral compartments of the lung.
  • particle sizes are selected depending on the site of desired deposition of the drug particles within the respiratory tract.
  • Aerosols useful in the invention include aqueous vehicles such as water or saline with or without ethanol and may contain preservatives or antimicrobial agents such as benzalkonium chloride, paraben, and the like, and/or stabilizing agents such as polyethyleneglycol.
  • Powders useful in the invention include formulations of the neat drug or formulations of the drug combined with excipients or carriers such as mannitol, lactose, or other sugars.
  • the powders used herein are effectively suspended in a carrier gas for administration.
  • the powder may be dispersed in a chamber containing a gas or gas mixture which is then inhaled by the patient.
  • the invention includes controlling deposition patterns and total dose through careful control of patient inspiratory flow and volume. This may be accomplished using the pulmonary devices described herein and similar devices. The inventors have shown by gamma scintigraphy measurements that drug aerosol deposition is maximized and evenly distributed in the peripheral lung when the patient inhales using slow flow rates and inhales to maximum lung volumes followed by brief breath holds.
  • Central lung deposition is favored when faster inspiratory flow rates and lower inspiratory volumes are used. Further, total deposited and regionally deposited doses are significantly changed as a patient's inspiratory patterns change. Therefore, the method of treatment and the use of the delivery devices described herein can be modified to target different regions of the respiratory tract and adjusted too deliver different doses of drug. It is the integration of drug molecular weight, protein binding affinity, formulation, aerosol generation condition, particle sized distribution, interface of aerosol delivery to the patient via the device and the control of the patient's inspiratory patterns that permit targeted and controlled delivery of highly toxic anti-cancer drugs to the respiratory tract with the option to minimize or provide controlled systemic availability of drug.
  • Example 3 The tests for administration of doxorubicin by inhalation referred to in Example 3 were substantially repeated at different dosages using a different drug administration system 500 described below.
  • eight dogs were used. The dogs were divided into two dose groups. A first group was the low dose group given a total daily dose of 60 mg/m 2 for three days or a total dose of 180 mg/m 2 . This resulted in a pulmonary deposition of about 90 mg/m 2 .
  • a high dose group was administered a dose of 180 mg/m 2 daily for three days or a total dose of 540 mg/m 2 . This resulted in a pulmonary deposition of about 270 mg/m 2 .
  • the purpose of the tests was to identify the maximum tolerated dose of inhaled drug.
  • active drug doses of doxorubicin of about 20 mg/m 2 , 180 mg/m 2 , and 270 mg/m 2
  • effective amounts of the active anticancer drugs can be from very small amounts to those where toxicity to normal tissue becomes a problem.
  • effective amounts and pharmaceutically effective amounts of antineoplastic drug deposited or applied to areas needing treatment are dosages that reduce a neoplasm or tumor mass, stop its growth or eliminate it altogether.
  • the liquid formulation was administered to the dogs by aerosolizing with a nebulizer exposure system 500 comprising a Pari LC Jet PlusTM nebulizer 501.
  • the nebulizer was filled with the solution of drug with which the dogs were to be treated.
  • the output of the nebulizer 501 was pulsed in a series of bursts over time (one pulse every ten seconds).
  • the nebulizer 501 was attached directly to a 460 cc volume plenum 503 and the plenum 503 was connected to a canine mouth only exposure mask 415 via a short piece of anesthesia tubing 505 and Y-fitting 507.
  • the mask 415 was tapered to approximately fit the shape of the dog's snout.
  • Means for enclosing the mouth and nose are of flexible material and are preferably held on by straps such as VelcroTM straps or belts.
  • Means for enclosing 601 has one end 603 for inserting the nose and mouth of the dog while the other end 605 has two openings 607,609 for attachment of nose outlet tube 611.
  • Nose outlet tube 611 has a one way valve 613 that allows the dog to exhale but not inhale through the its nose.
  • Mouth tube 621 is inserted and attached to opening 609 and lies within the means for enclosing 601.
  • An optional Y- connector 623 may be attached and used with mouth tube 621 for providing and receiving inhaled and exhaled gases.
  • Air is generally inhaled through leg 625 of the Y-connector 623. The air passes through the mouth tube 621 and out the inner opening 631 into the respiratory system of the dog. Inner opening 631 is cut at an angle with its lower portion 633 extending further into the mouth of the dog than the upper portion 635. Lower portion 633 functions to depress the tongue of the dog and allow more efficient flow of air and aerosol into the dog.
  • Means for enclosing 601 effectively seals the dog's mouth and nose from outside air.
  • a nose outlet tube 611 has been found to greatly ease the dogs wearing of the mask. Air exhaled through the mouth exits mouth tube 621 and passes into optionally attached Y-connector or to another tube not shown. Air exits Y connector 623 via outlet tube 627. If desired the Y-connector 623 or other outer tube (e.g. straight tubing) may be made of one piece and simply pass into the enclosing means 601 or may be of separate pieces that fit together. In either case an adapter 637 may be used to hold the mouth tube 621 and or other tubing to which it is connected.
  • Y-connector 623 or other outer tube e.g. straight tubing
  • an adapter 637 may be used to hold the mouth tube 621 and or other tubing to which it is connected.
  • a general device for administering aerosols to a patient includes an inhalation mask for administering aerosols to the including means for enclosing the mouth and nose of the patient, having an open end and a closed end, the open end adapted for placing over the mouth and nose of the patient; upper and lower holes in the closed end adapted for insertion of a nose outlet tube and a mouth inhalation tube; the nose outlet tube attached to the upper hole, adapted to accept exhaled breath from the nose of the patient; a one way valve in the nose tube adapted to allow exhalation but not inhalation; the mouth inhalation tube having an outer and an inner end, partially inserted through the lower hole, the inner end continuing to end at the rear of the patients mouth, the inhalation tube end cut at an angle so that the lower portion extends further into the patients mouth than the upper portion and adapted to fit the curvature of the rear of the mouth; and a y- adapter attached to the outer end of the mouth inhalation tube.
  • Pulmonary administration by inhalation may be accomplished by means of producing liquid or powdered aerosols, for example, by the devices disclosed herein or by using any of various devices known in the art.
  • the devices disclosed herein or by using any of various devices known in the art.
  • PCT Publication No. WO 92/16192 dated October 1, 1992; PCT Publication No. WO 91/08760 dated June 27, 1991; NTIS Patent Application 7-504-047 filed April 3, 1990 by Roosdorp and Crystal including but not limited to nebulizers, metered dose inhalers, and powder inhalers.
  • Ultravent nebulizer (Mallinckrodt, Inc, St. Louis, MO); Acorn II nebulizer (Marquest Medical Products, Englewood, CO); Ventolin metered dose inhalers (Glaxo Inc., Research Triangle Park, North Carolina); Spinhaler powder inhaler (Fisons Corp., Bedford, MA) or Turbohaler (Astra).
  • Ultravent nebulizer Melinckrodt, Inc, St. Louis, MO
  • Acorn II nebulizer Marquest Medical Products, Englewood, CO
  • Ventolin metered dose inhalers (Glaxo Inc., Research Triangle Park, North Carolina); Spinhaler powder inhaler (Fisons Corp., Bedford, MA) or Turbohaler (Astra).
  • Such devices typically entail the use of formulations suitable for dispensing from such a device, in which a propellant material may be present.
  • Ultrasonic nebulizers may also be used. Nebulizer devices such as those in Greenspan et al US patents
  • 5,511,726 and 5,115,971 are useful in the invention. These devices use electrohydrodynamic forces to produce a finely divided aerosol having uniformly sized droplets by electrical atomization. While the Greenspan devices use piezoelectric materials to generate electrical power any power source is acceptable to produce the electrohydrodynamic forces for nebulization.
  • a nebulizer may be used to produce aerosol particles, or any of various physiologically inert gases may be used as an aerosolizing agent.
  • Other components such as physiologically acceptable surfactants (e.g. glycerides), excipients (e.g. lactose), carriers (e.g. water, alcohol), and diluents may also be included.
  • a major criteria for the selection of a particular device for producing an aerosol is the size of the resultant aerosol particles. Smaller particles are needed if the drug particles are mainly or only intended to be delivered to the peripheral lung, i.e. the alveoli (e.g. 0.1-3 ⁇ m), while larger drug particles are needed (e.g. 3-10 ⁇ m) if delivery is only or mainly to the central pulmonary system such as the upper bronchi. Impact of particle sizes on the site of deposition within the respiratory tract is generally known to those skilled in the art. See for example the discussions and figures in the articles by Cuddihy et al (Aerosol Science; Vol.
  • a nebulizer apparatus 700 that is preferably portable for administration of drug to a patient in need of therapy.
  • the nebulizer apparatus 700 is used in combination with the highly toxic drugs of the present invention and with drugs having properties adapted for optimum treatment of neoplasms as discussed elsewhere herein.
  • Figure 7 is a schematic of a nebulizer combination according to the present invention.
  • Nebulizer 701 may be any nebulizer as described earlier herein that is able to produce the particle sizes needed for treatment.
  • a highly toxic drug formulation 703 for treatment of neoplasms as disclosed herein.
  • An air supply 705 is provided either as a tank of compressed gas or as a motorized pump or fan for moving air from the room.
  • An optional mouthpiece 707 may be used where it is necessary to provide sealed contact between the nebulizer and the patient.
  • the mouthpiece 707 may be molded as part of nebulizer 701.
  • Power for use of the nebulizer apparatus 700 may come from the compressed gas from hand manipulation by the user or administrator or by batteries or electrical power not shown but well known by those skilled in the art.
  • the patient may be placed in a well-ventilated area with exhaust air filtered to remove antineoplastic drug that escapes from the device.
  • Examples 5F to 11F show inhalation feasibility and proof of concept tests and Examples 5R to 10R show dose escalation range tests with: vesicant antineoplastic drugs including doxorubicin, paclitaxel, vincristine, vinorelbine; nonvesicant drugs including etoposide, and 9-aminocampothecin (9-AC) and carboplatin.
  • vesicant antineoplastic drugs including doxorubicin, paclitaxel, vincristine, vinorelbine
  • nonvesicant drugs including etoposide, and 9-aminocampothecin (9-AC) and carboplatin.
  • the drugs were delivered to the pulmonary system via aerosol at a particle size of about 2 to about 3 ⁇ m.
  • the drugs were delivered in water or other vehicles appropriate for the drug as is known in the art and as exemplified herein.
  • Table 7 illustrates the dosage schedule for the range-finding studies. A minimum of 7-14 days separated each escalating dose. No range finding tests, only feasibility tests, were performed for mitomycin-C and 9-AC. No feasibility tests, only dose range-finding tests, were performed for vinorelbine. It is important to note that the doses listed in Table 7 are the pulmonary deposited doses not the total doses administered.
  • IV intravenous
  • the IV dose given was typically the usual human clinical dose that had been scaled down for the dogs based on differences in body mass, or the maximum tolerated dose in the dog, whichever is greater.
  • An average human having a weight of 70kg is considered to have a weight to body surface ratio of 37 kg/m 2 and a lung surface area of 70 - 100 m 2 of lung surface area.
  • the average dog used in the tests was considered to have a weight of 10kg corresponding and a weight to body surface ratio of 20 kg/m 2 and a lung surface area of 40 - 50 m 2 lung surface area (CRC Handbook of Toxicology, 1995, CRC Press Inc.).
  • the single IV dose was used to quantify the plasma kinetics. With most of the cytotoxic agents treated, the single IV dose resulted in a predictable mild decrease in white blood cell counts, with no other measurable toxicities.
  • the dogs were allowed a washout period of at least seven days (until the dogs returned to normal conditions) before they were treated with inhaled antineoplastic drugs.
  • the dogs were generally exposed to a dose of inhaled antineoplastic drug in aerosol form once per day for three consecutive days (except as noted in Tables 8 to 11) and necropsied one day following the last dose with the plasma kinetics characterized after the first and third exposures.
  • the drugs did not exhibit any significant pulmonary toxicity in these repeated exposure inhalation feasibility studies.
  • the dogs used the same mask and apparatus used for the earlier examples.
  • the dogs were fitted with an endo-tracheal tube and the drug administered as an aerosol directly from the endo-tracheal tube. This latter procedure made it easier to control the pulmonary deposited dose since the aerosol was released directly into the pulmonary air passages assuring deep deposition of the drug in the lung.
  • use of the endo-tracheal tube made it possible to do the tests in a shorter time since the dogs needed a four to six week training period to properly acclimate to and use the masks.
  • the calculated deposited doses obtained herein were verified experimentally by pulmonary scintigraphy tests in dogs.
  • this table shows the details of the feasibility test of paclitaxel.
  • the dogs were administered 120 mg/m 2 of paclitaxel by IV.
  • the dogs were administered a total deposited dose of 120 mg/m 2 of paclitaxel, by inhalation, three times for a total deposited dose of 360mg/m 2 .
  • This administered dose resulted in a pulmonary deposited dose of about 27 mg each time or a total pulmonary dose of about 81 mg. This represents a total pulmonary deposited dose of about 2.1 mg/m 2 of lung surface area.
  • the dosages were calculated as follows: the dose of 120 mg/m 2 was divided by 20 kg/m 2 to yield a 6 mg/kg dose that was multiplied by 10 kg for the average dog to yield about 60 mg of drug. Since the dogs were using the masks for drug administration, one half or about 30 mg of drug was considered deposited in the deep lung. Since the drug was administered three times the total drug exposure was about 90 mg. The 90 mg of drug was divided by 40 to yield a total dose to the lung of about 2.25 mg/m 2 lung surface area.
  • the histopathology reflects that normally found in IV administration of paciitaxel particularly GI inflammation and ulceration which is probably associated with systemically administered paclitaxel. Respiratory tract toxicity indicated minimal pulmonary interstitial inflammation. Systemic bioavailability was proportional to dose. The probable dose limiting toxicity is myelosuppression and GI toxicity, and not pulmonary toxicity.
  • doxorubicin 20 mg were initially administered by IV. After the washout period three sets of inhalation feasibility tests were made. In the first, a single dose of 20 mg/m 2 of doxorubicin was administered that gave about a 10 mg body dose, a pulmonary deposited dose of about 5 mg or about 0.125 mg/m 2 lung surface area. No changes were noted in the animal from this dose. A second set of moderate inhalation dosages of about 40 mg/m 2 of doxorubicin (about 10 mg deposited within the lung) was administered three times a day for three consecutive days.
  • Total cumulative dose administered was 120 mg/m 2 corresponding to a about a 60 mg body dose, and a total pulmonary deposited dose of about 30 mg (or about 0.75 mg/m 2 of lung surface area).
  • a third set of high inhalation dosages of 120 mg/m 2 of doxorubicin was administered three times per day over a three day period for a total dose of 360 mg/m 2 corresponding to a 180 mg body dose, a total pulmonary deposited dose of about 90 mg or about 2.25 mg/m 2 of lung surface area.
  • One half of the low dose group dogs was necropsied the day after the final exposure and the remaining half was necropsied four days later. All high dose dogs were necropsied the day after the final exposure.
  • Plasma levels of doxorubicin were dose dependent and exhibited clear evidence of drug accumulation, including daily increases in Cmax (maximum concentration in blood) and steady state-like profiles, suggesting there was a rate limited absorption from the lung into the blood with significant accumulation of doxorubicin in the lungs following each additional exposure given at a frequency of daily intervals. This accumulation was considered likely responsible for the tissue damage observed.
  • an inhalation dose range of 20-40 mg/m 2 was administered in five weekly doses that resulted in a body exposure of about 10 mg to about 20 mg, a pulmonary deposited dose range of about 10 to about 20 mg or a range of about 0.25 mg/m 2 to about 0.5 mg/m 2 lung surface area.
  • the clinical condition included increased respiratory rate and mild transient pulmonary edema. A decrease in white blood cell count was noted for the higher dosages. Histopathology revealed mild to moderate thoracic and mesenteric lymphoid depletion. Respiratory tract toxicity noted was mild to moderate degeneration of airway epithelium. A mild to moderate to marked interstitial inflammation was noted with some limited fibrosis. Bioavailability was noted to be low to moderate with absorption being rate limited. The probable dose limiting toxicity appears again to be respiratory tract toxicity.
  • Vinorelbine which is also a vinca alkaloid was evaluated in a repeated exposure pilot tests. Compared to vincristine, vinorelbine was approximately 5-10 times less potent in producing toxicity, but produced similar types of changes. Vinorelbine delivered by pulmonary administration directly into the lungs of dogs by endotracheal tube, on a weekly basis (for 5 weeks) at escalating doses was well tolerated. A dose of 6 mg deposited in the lung was initially selected and escalated to 15 mg deposited within the lung. This represented a lung surface exposure of ⁇ 0.15-0.375 mg/m 2 of lung surface area and total body doses of 12-30 mg/m 2 . This treatment regimen produced very minimal effects within the respiratory tract, characterized principally by slight inflammation.
  • inhaled vinorelbine produced sufficient blood levels to cause mild to moderate myelosuppression and lymphoid depletion, both of which were reversible and of a severity, which was not life-threatening.
  • Etoposide is a cytotoxic drug, representative of a class of drugs known as topoisomerase II inhibitors. Given orally or IV, etoposide causes typical cytotoxic systemic toxicity, including myelosuppression, severe GI toxicity and alopecia. Etoposide is a highly insoluble drug and therefore difficult to formulate. The vehicle used clinically also causes adverse effects, predominantly anaphylactic type reactions.
  • etoposide was reformulated in a novel vehicle, dimethylacetamide (DMA) which does not cause anaphylactic reactions. While DMA cannot be used for IV administration due to systemic toxicity, it was shown to be a safe delivery vehicle for the pulmonary route of delivery.
  • the etoposide was delivered in a 100% DMA vehicle. This formulation allowed the formation of the appropriate particle sizes. In these tests, escalating doses of etoposide were given to dogs on a weekly schedule. The initial dose used was 25 mg of etoposide deposited in the pulmonary region with a 6 th and final dose delivered of 80 mg deposited within the pulmonary region.
  • DMA dimethylacetamide
  • a single inhaled total deposited dose of 260 mg/m 2 (about 65 mg of drug deposited in the pulmonary region) produced blood levels of etoposide similar to an IV dose of 50 mg/m 2 (see Figures 1-3). In other words, to reach similar blood concentrations approximately 5X more drug was given by inhalation, a dose which caused neither respiratory tract nor systemic toxicity.
  • Example 10F
  • CTX cyclophosphamide
  • QW every week
  • the paclitaxel is administered with 0.2% of citric acid to prevent degradation of the drug unless it is immediately used after preparation.
  • the treatments were administered once every two weeks, and if a diagnosis of progressive disease was made on two consecutive intervals the dog was crossed over to the alternate drug.
  • blood was sampled for hematology and biochemical analyses and urine was collected for analysis. The status of the tumors was monitored radiographically.
  • the last group of dogs are those that had primary lung tumors which were removed surgically. These dogs had metastases in their thoracic lymph nodes and have a life expectancy measured in weeks. As shown in Table 13, two dogs (Examples 31 and 32) received doxorubicin by inhalation (1.5 mg) and two dogs (Example 33) received paclitaxel (20 mg). The dog that received five treatments of doxorubicin was alive with no evidence of disease 81 days later suggesting that the treatment is having a positive effect. One dog (Example 32) received two doses of doxorubicin and died from metastases outside of the lung. The other two dogs (Example 33) have no evidence of disease but not enough time has passed to determine how effective the treatment will be.
  • DOX doxorubicin
  • ( x) number of treatments received
  • SD stable disease
  • PD progressive disease
  • NED no evidence of disease
  • PR partial response (50% decrease in tumor size)
  • Table 14 The safe and effective range of doses of the inhalant antineoplastic drugs in humans and animals (e.g. dogs and similar small animals) are shown in Table 14 below. Larger animal dosages can be calculated by using multiples of the small animal based dose based on the known relationship of (body weight in kg/m 2 of body surface area. The exact doses will vary depending upon such factors as the type and location of the tumor, the age and size of the patient, the physical condition of the patient and concomitant therapies that the patient may require.
  • the dosages shown are for doses for one course of therapy, that is, for an individual treatment session.
  • a course of therapy may be given, monthly, weekly, biweekly, triweekly or daily depending on the drug, patient, type of disease, stage of the disease and so on.
  • Exemplary safe and effective amounts of carrier for each product have been published by the respective manufacturer and are summarized in the Physicians Desk Reference, although, some may not be amenable to inhalation therapy.
  • a safe and effective amount of a particular drug or agent is that amount which based on its potency and toxicity, provides the appropriate efficacy/risk balance when administered via pulmonary means in the treatment of neoplasms.
  • a safe and effective amount of a vehicle or carrier is that amount based on its solubility characteristics, stability, and aerosol forming characteristics, that provides the required amount of a drug to the appropriate site in the pulmonary system for treatment of the neoplasm.
  • nonvesicant antineoplastic drugs based on the inhalation tests herein for the vesicating and nonvesicating drugs it is expected that all the nonvesicating drugs that do not exhibit direct pulmonary toxicity when administered intravenously are expected be well tolerated and exhibit efficacy. Bleomycin and mitomycin-C, for example, exhibit sufficient pulmonary toxicity to be excluded except when a chemoprotectant is used.
  • carmustine, dacarbazine, melphalan, methotrexate, mercaptopurine, mitoxantrone, esorubicin, teniposide, aclacinomycin, plicamycin, streptozocin, menogaril are expected to be well tolerated and exhibit efficacy.
  • drugs of presently unknown classification such as geldanamycin, bryostatin, suramin, carboxyamido-triazoles such as those in US patent 5,565,478, onconase, and SU101 and its active metabolite SU20 are likewise expected to be well tolerated and exhibit efficacy subject to the limitation on pulmonary toxicity.
  • Paclitaxel (Bristol-Meyers Squibb) pp. 723-727 - vesicant, pulmonary toxicity is not listed for paclitaxel, but dose limiting bone marrow suppression (primarily neutropenia) is important; • Bleomycin (Blenoxane® Bristol-Meyers Squibb) pp.
  • Irinotecan (Camptosar® Pharmacia & Upjohn) - a derivative of camptothecin, primary toxicity appears to be severe diarrhea and neutropenia, no mention is made of pulmonary toxicity making the drug useful in the present invention
  • An additional embodiment of the invention includes methods and formulations that contain chemoprotectants and are administered by inhalation for preventing toxicity and particularly pulmonary toxicity that may be elicited by antineoplastic drugs.
  • the method would allow the use by inhalation of antineoplastic drugs that exhibit pulmonary toxicity or would reduce the likelihood of pulmonary toxicity.
  • One method would include treating a patient having a neoplasm, via inhalation administration, a pharmaceutically effective amount of a highly toxic antineoplastic drug and a pharmaceutically effective amount of a chemoprotectant, wherein the chemoprotectant reduces or eliminates toxic effects in the patient that are a result of inhaling the highly toxic antineoplastic drug.
  • another embodiment includes a combination of inhaled chemoprotectant and antineoplastic drug that reduces or eliminates respiratory tract or pulmonary tract toxicity in the patient.
  • the chemoprotectant can be coadministered with the antineoplastic drug by inhalation, or both by inhalation and by IV, or the chemoprotectant can be administered alone.
  • dexrazoxane when given by intraperitoneal injection to mice is protective against pulmonary damage induced by bleomycin given by subcutaneous injections. See for example Herman, Eugene et al, "Morphologic and morphometric evaluation of the effect of ICRF-187 on bleomycin-induced pulmonary toxicity", Toxicology 98, (1995) pp. 163-175, the text of which is incorporated by reference as if fully rewritten herein.
  • Dexrazoxane (ICRF-187) is dissolved in a pharmaceutically acceptable liquid formulation and administered to a patient as an aerosol using the apparatus and methods described herein, at a dose ranging from 10 mg to 1000 mg over a period of from one minute to one day prior to giving a chemotherapeutic drug such as doxorubicin by inhalation.
  • the doxorubicin is given in a dose from 1 mg to 50 mg.
  • Dexrazoxane (ICRF-187) is administered as described in Example 34 at the same time or up to two hours before giving bleomycin by intravenous injection.
  • the dose of dexrazoxane ranges form about 2 times to about 30 times the dose of bleomycin.
  • the dose of bleomycin by IV ranges from about 5 to 40 units/m 2 .
  • Example 36 Dexrazoxane (ICRF-187) is administered as described in Example 34 at the same time or up to two hours before administering bleomycin by inhalation.
  • the dose of dexrazoxane ranges from about 2 times to about 30 times the dose of bleomycin.
  • the dose of bleomycin by inhalation ranges from 5 to 40 units/m 2 at intervals of from 1 week to 4 weeks.
  • Chemoprotectants such as mesna (ORG-2766), and ethiofos (WR2721) may be used in a manner similar to that described in Examples 34 to 36, above.
  • Another embodiment of the invention contemplates drug coadministration by the pulmonary route, and by (1) other local routes, and/or (2) systemically by IV. Results from the clinical tests on dogs indicates that, although the pulmonary route of administration will indeed control neoplastic cells arising in or metastatic to the pulmonary tract, neoplastic cells elsewhere in the body may continue to proliferate.
  • This embodiment provides for effective doses of drug in the lung delivered via the lung and additional drug delivered via (1) other local sites (e.g. liver tumors may also be treated via hepatic artery instillation, ovarian cancer by intraperitoneal administration) and/or additional drug(s) may be provided systemically by IV via the general circulatory system.
  • Administration can be at the same time, or administration followed closely in time by one or more of the other therapeutic routes. Benefits are that much higher dosages can be supplied to affected tissues and effective control of neoplasms can be maintained at multiple critical sites compared to using a single mode of administration.
  • Also contemplated within the scope of the invention is the combination of drugs for combination chemotherapy treatment.
  • Benefits are those well known in the treatment of cancer using combination chemotherapy by other routes of administration.
  • combining drugs with different mechanisms of action such as an alkylating agent plus a mitotic poison plus a topoisomerase inhibitor.
  • Such combinations increase the likelihood of destroying tumors that are comprised of cells with many different drug sensitivities. For example, some are easily killed by alkylating agents while mitotic poisons kill others more easily.
  • inventions comprising the method for inhalation therapy disclosed herein and the application of radiotherapy, gene therapy, and/or immunotherapy.
  • Other embodiments include the immediately above method combined with chemotherapy applied by IV and/or local therapy.
  • formulations for paclitaxel are included within the invention.
  • 100% to 40% ethanol is useful.
  • PEG polyethylene glycol
  • a further embodiment also includes the addition of 0.01 to 2% of an organic or inorganic acid, preferably an organic acid such as citric acid and the like. The acid being added to stabilize the formulation.
  • citric acid in water has been found to cause tussive and bronchioconstrictive effects. PEG may ameliorate this effect.
  • the formulation contains a safe and effective amount of paclitaxel useful for the treatment of neoplasms.
  • Splenic hemangiosarcoma is recognized as disease that almost invariably results in metastatic disease with a very high incidence of metastases in the lung.
  • dogs with micrometastatic splenic hemangiosarcoma underwent surgery (splenectomy) to remove the primary tumor followed by inhalation chemotherapy with concomitant or concurrent systemic chemotherapy.
  • Dogs selected for the tests were selected to have no signs of metastasis to the lung or gross abdominal metastasis as determined by radiographic techniques. Each dog was exposed to inhalation to an aerosol concentration of an antineoplastic drug that would deposit drug in the pulmonary region (based on a 65 percent deposition fraction).
  • the eight dogs tested were dogs that had spontaneously arising cancers.
  • the dogs are designated A through M with the letters M or F after this designation referring to male or female respectively, N stands for neutered, and the last number is the age in years.
  • the dogs were mostly older dogs the youngest being 4 years old and the oldest 14 years (average and median ages were both 10).
  • the dogs were a variety of breeds with the weight ranging from 2 to 49 kg.
  • the actual method of treatment for the tests of Table 15 were as follows: (a) the primary tumor was treated by surgical excision; (b) following surgical excision (two weeks after surgery) the dogs are scheduled to receive four cycles of standard systemic chemotherapy (doxorubicin 30 mg/m 2 IV and cyclophosphamide 150 mg/m 2 IV) at three week intervals (Note: one dog was treated on the day of surgery with doxorubicin by inhalation with the remainder of the dogs being treated about two weeks later); (c) concurrent with systemic therapy, the dogs receive four treatments of doxorubicin inhalation therapy. It is noted Those skilled in the art will appreciate that the methods presented herein, although only tested on dogs, will have general applicability to humans and other animals.
  • the method for treating a patient for a neoplasm and preventing pulmonary metastasis includes the steps of (a) treating the patient for the neoplasm wherein the treatment is selected from the group consisting of partial or complete surgical excision, radiation therapy, local-regional chemotherapy, immunotherapy, gene therapy and combinations thereof; (b) administering an effective amount of systemic chemotherapy; and (c) concurrently administering an effective amount of chemotherapy by inhalation.
  • Local-regional chemotherapy includes for example local treatments such as injections of antineoplastic drugs into the tumor, the organ (e.g. prostate) or spine , infusions into the bladder, and the like.
  • Systemic chemotherapy includes parenteral administration wherein the administered drug enters the general circulation.
  • systemic chemotherapy is of course intravenous injection of antineoplastic drugs, however, other methods of parenteral administration can result in effective systemic distribution of the drugs.
  • An effective amount of systemic chemotherapy and an effective amount of chemotherapy by inhalation is considered to be the level of antineoplastic drug administered by each mode that results in elimination of metastasis or at least reduced incidence of metastasis.
  • Concomitant or concurrent chemotherapy by systemic and inhalation modes of administration contemplates administration such that the two modes of administration have a synergistic effect when used together compared to either being used alone. This is usually obtained by administration of the antineoplastic drugs close in time.
  • a preferred method of administration is to have the drugs administered by inhalation and systemically at the same time or approximately the same time.
  • chemotherapy by inhalation could be administered shortly before, during, or after systemic chemotherapy.
  • the drugs are administered by each mode within one week of each other and most preferably within a few days or the same day.
  • the dosages for IV administration when used in combination with inhalation therapy as described herein are typically those usually used for current treatment by IV alone. Dosages for IV administration for particular drugs may be determined from the Physicians Desk Reference cited above. While the forms of the invention herein disclosed constitute presently preferred embodiments, many others are possible. It is not intended herein to mention all of the possible equivalent forms or ramifications of the invention. It is to be understood that the terms used herein are merely descriptive, rather than limiting, and that various changes may be made without departing from the spirit of the scope of the invention.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Communicable Diseases (AREA)
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  • Pulmonology (AREA)
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Abstract

L'invention porte sur des procédés et préparations prévenant et traitant les néoplasmes métastatiques des voies pulmonaires, en agissant par exemple sur les cancers survenant dans d'autres parties du corps et qui induisent des métastases dans les poumons, moyennant un traitement concomitant par injections intraveineuse de médicaments antinéoplasmiques et inhalation de médicaments antinéoplasmiques.
PCT/US1999/022845 1998-10-02 1999-10-01 Chimiotherapie par inhalation pour la prevention et le traitement des tumeurs metastatiques du poumon WO2000019991A1 (fr)

Priority Applications (2)

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AU12001/00A AU1200100A (en) 1998-10-02 1999-10-01 Inhalation chemotherapy for prevention and treatment of metastatic tumors in thelung
CA002346029A CA2346029A1 (fr) 1998-10-02 1999-10-01 Chimiotherapie par inhalation pour la prevention et le traitement des tumeurs metastatiques du poumon

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US16586498A 1998-10-02 1998-10-02
US09/165,864 1998-10-02

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WO2001066103A3 (fr) * 2000-03-03 2002-03-21 Battelle Memorial Institute Formulation et methode de traitement des neoplasmes par inhalation
US7090830B2 (en) 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
WO2008134630A1 (fr) * 2007-04-30 2008-11-06 Apt Pharmaceuticals Composés de dexrazoxane pour une cardioprotection
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
US7537009B2 (en) 2001-06-05 2009-05-26 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US7540286B2 (en) 2004-06-03 2009-06-02 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US7581540B2 (en) 2004-08-12 2009-09-01 Alexza Pharmaceuticals, Inc. Aerosol drug delivery device incorporating percussively activated heat packages
US7585493B2 (en) 2001-05-24 2009-09-08 Alexza Pharmaceuticals, Inc. Thin-film drug delivery article and method of use
US8991387B2 (en) 2003-05-21 2015-03-31 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US12214119B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device

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US5283383A (en) * 1992-02-13 1994-02-01 The United States Of America As Represented By The Department Of Health And Human Services Antitumor compound, compositions and method of use
EP0709090A2 (fr) * 1994-10-14 1996-05-01 Eli Lilly And Company Compositions pour le traitement de tumeurs résistantes
WO1998029110A2 (fr) * 1996-12-30 1998-07-09 Battelle Memorial Institute Preparation et methode de traitement de neoplasmes par inhalation

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Publication number Priority date Publication date Assignee Title
US5283383A (en) * 1992-02-13 1994-02-01 The United States Of America As Represented By The Department Of Health And Human Services Antitumor compound, compositions and method of use
EP0709090A2 (fr) * 1994-10-14 1996-05-01 Eli Lilly And Company Compositions pour le traitement de tumeurs résistantes
WO1998029110A2 (fr) * 1996-12-30 1998-07-09 Battelle Memorial Institute Preparation et methode de traitement de neoplasmes par inhalation

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001066103A3 (fr) * 2000-03-03 2002-03-21 Battelle Memorial Institute Formulation et methode de traitement des neoplasmes par inhalation
US7585493B2 (en) 2001-05-24 2009-09-08 Alexza Pharmaceuticals, Inc. Thin-film drug delivery article and method of use
US7090830B2 (en) 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US10350157B2 (en) 2001-05-24 2019-07-16 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9440034B2 (en) 2001-05-24 2016-09-13 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9211382B2 (en) 2001-05-24 2015-12-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
US9687487B2 (en) 2001-06-05 2017-06-27 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US8955512B2 (en) 2001-06-05 2015-02-17 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US11065400B2 (en) 2001-06-05 2021-07-20 Alexza Pharmaceuticals, Inc. Aerosol forming device for use in inhalation therapy
US9308208B2 (en) 2001-06-05 2016-04-12 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US7537009B2 (en) 2001-06-05 2009-05-26 Alexza Pharmaceuticals, Inc. Method of forming an aerosol for inhalation delivery
US9439907B2 (en) 2001-06-05 2016-09-13 Alexza Pharmaceutical, Inc. Method of forming an aerosol for inhalation delivery
US7458374B2 (en) 2002-05-13 2008-12-02 Alexza Pharmaceuticals, Inc. Method and apparatus for vaporizing a compound
US8991387B2 (en) 2003-05-21 2015-03-31 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US9370629B2 (en) 2003-05-21 2016-06-21 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US7540286B2 (en) 2004-06-03 2009-06-02 Alexza Pharmaceuticals, Inc. Multiple dose condensation aerosol devices and methods of forming condensation aerosols
US7581540B2 (en) 2004-08-12 2009-09-01 Alexza Pharmaceuticals, Inc. Aerosol drug delivery device incorporating percussively activated heat packages
US11642473B2 (en) 2007-03-09 2023-05-09 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
US12138383B2 (en) 2007-03-09 2024-11-12 Alexza Pharmaceuticals, Inc. Heating unit for use in a drug delivery device
WO2008134630A1 (fr) * 2007-04-30 2008-11-06 Apt Pharmaceuticals Composés de dexrazoxane pour une cardioprotection
US12214119B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device
US12214118B2 (en) 2018-02-02 2025-02-04 Alexza Pharmaceuticals, Inc. Electrical condensation aerosol device

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CA2346029A1 (fr) 2000-04-13

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