MXPA99006122A - Formulation and method for treating neoplasms by inhalation - Google Patents

Abstract

A formulation, method, and apparatus for treating neoplasms such as cancer by administering a pharmaceutically effective amount of highly toxic composition by inhalation, wherein the composition is a non-encapsulated antineoplastic drug.

Description

* t 1 FORMULATION AND METHOD FOR TREATING NEOPLASMS BY INHALATION The invention relates to formulations and methods useful for treating neoplasms, particularly neoplasms of the respiratory tract (e.g., lung cancer and cancers of the head and neck), by pulmonary administration of anti-inflammatory drugs. highly toxic carcinogens or vesicants. Additionally, several new formulations and methods are also described for treating neoplasms using antineoplastic drugs that are non-vesicant. BACKGROUND OF THE I NVENTION Cancer is one of the leading causes of death worldwide. In particular, lung cancer is among the 3 5 most prevalent cancers and has a very poor survival regime (around 13% survival rate in five years). Despite the availability of many cancer drugs, it has been difficult and, in the case of some types of cancer, it is almost impossible to improve the cure or survival rates. There are 0 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 toxicities that weaken and threaten the life of the patient. In addition, most of the chemotherapeutic drugs used to treat cancer are highly toxic to normal and tumor tissues.

In the treatment of cancer, it is common to administer drugs through the intravenous route, which exposes the entire body to the drug. The doses are selected in a manner that destroys tumor cells, but these doses also destroy normal cells. As a result, the patient usually experiences severe toxic side effects. For example, severe myelosuppression may result, which includes the patient's ability to resist infection and allows the spread of the tumor. There are other life-threatening effects such as hepatotoxicity, renal toxicity, pulmonary toxicity, cardiac toxicity, neurotoxicity and gastrointestinal toxicity used by anti-carcinogenic drugs. Anti-carcinogenic drugs also cause other defects such as alopecia, stomatitis and cystitis that may not threaten life, but are serious enough to affect the patient's quality of life. In addition, it is important to note that these toxicities are not associated to the same degree with all anti-carcinogenic drugs but are due to the systemic supply of the drug. Although myelosuppression is commonly associated with most anti-carcinogenic drugs, due to differences in the mechanisms by which various anti-cancer drugs act or in the way they are distributed in the body, they are metabolized and excreted from the body Each drug has a somewhat different toxicity profile, both quantitatively and qualitatively. For example, anthracyclines such as doxorubicin, epirubicin and idarubicin are known to cause severe cardiac toxicity. Additionally, doxorubicin is known to cause progressive tissue necrosis when extravasated. It is known that cisplatin therapy causes renal toxicity; vincristine causes neurotoxicity, bleomycin and mitomycin cause pulmonary toxicity, cyclophosphamide causes cystitis; and 5-fluorouracil results in brain disjunction (see Cancer Chemotherapy: Principles and Practice, BA Shabner and J. M. Collings, eds J B. Lippincott Co., Philadelphia, 1990). The differences in the mechanisms of action and pharmacokinetic properties determine, in part, the efficacy of several anti-carcinogenic drugs against different tumor types, which exhibit several biological behaviors. Several attempts have been made to deliver anti-cancer drugs directly to the tumor or to the tumor region to minimize the exposure of normal tissues to the drug. This regional therapy, for example, has been used to treat live cancer by delivering drugs directly to the liver artery so that the full dose reaches the liver while reducing the amount going to the rest of the body. For the treatment of urinary bladder cancer, anti-carcinogenic drugs are instilled directly into the bladder through the urethra, allowing to remain in contact with the tumor for a while and then removed n. Other examples of therapy in the region include the supply of anti-carcinogenic drugs in the peritoneal cavity to treat cancer that has developed or metastasized there. Other methods can direct anticancer drugs that involve the binding of drugs to bodies that seek to remove and deliver the drug directly to cancer cells. In 1968 Shevchenko, I.T. , (Neoplasm 15, 4, 1968) p. 419-426, reported the treatment of advanced bronchial cancer using a combination of inhalation of chemotherapeutic agents, radiotherapy and oxygen inhalation. The chemotherapeutic agents reported were benzotaf, thiophosphamide, cyclophosphamine and endoxan that were applied as an aerosol by means of an inhaler. For 58 treated patients, the combination of three treatments showed disappearance of the tumor in 8 cases while in 6 the size of the tumor decreased considerably. The study did not include a control group. In 1970, Sugawa, I. (Ochanoizu Med. J.; Vol; No. 3; (1970), pgs. 103-1 14, reported evidence using mitomycin-C in the treatment of metastatic lung cancer. One of four treated patients reported some improvement reportedly. Inhalation of mitomycin-C also appeared to reduce tumor growth in tumors inoculated by IV in rabbits. The results appeared to be more inconclusive in rats. The tests were carried out to determine the toxic effects to the respiratory tract after intrabronchial infusions of several drugs. Drugs were given to healthy animals and included: thiotepa (rats), Toyomycin (chromomycin A3) (rats), endoxan (cyclophosphamide (rats and rabbits), 5-fluorouracil (rats and rabbits), mitomycin-C (rats, rabbits and dogs) The results of these tests showed that: 5-FU and cyclophosphamide resulted only in moderate inflammation, thiotepa bronchial obstruction product, chromomycin A3 and mitomycin-C produced the most severe results.The toxic effects of mitomycin-C and chromomycin A3 they were studied in rabbits and dogs.In 1983, Tatsumura et al. (Jp Cancer Cln. Vol. 29, pp. 765-770) reported that the anti-carcinogenic drug, fluorouracil (5-FU, MW = 130), It was effective for the treatment of lung cancer in a small group of human patients when administered directly to the lung by aerosolization, referred to as nebulization chemotherapy, and was also observed by Tatsumura et al. (1993) (Br. J. , Vol. 68 (6): pp.1 146-1 149), that 5-FU did not cause lung toxicity. This finding was not totally unexpected because 5-FU has a very low molecular weight and does not bind tightly to proteins. Therefore, it passes through the lung rapidly decreasing the opportunity to cause local toxicity. In addition, 5-FU is considered one of the least toxic anti-carcinogenic drugs when applied directly to tissue. In addition, 5-FU was used as a topical drug for the treatment of actinic keratosis, for which it is applied liberally, twice a day, to lesions on the face. This therapy can 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 can be inadvertently passed and has access to the bloodstream from the intestine. It is well known that a large percentage of aerosolized drug destined for the lung is passed through the throat. Another report includes the use of β-cytosine arabinoside (Ara-C, cytarabine, PM = 243) administered via intratracheal delivery to the respiratory system of rats. The encapsulated liposome and free Ara-C were installed intratracheally to the rats as a bolus. The encapsulated Ara-C persisted for a long time in the drug while free Ara-C that is not highly bound to the proteins was rapidly eliminated from the lung. The free Ara-C rapidly diffused through the mucosa of the lung and entered the systemic circulation. The paper suggests that the encapsulation of drug liposomes may be a way to produce local pharmacological effect within the lung without producing adverse side effects in other tissues. However, bolus administration results in concentrated multifocal drug bags. See the articles by H. N. MacCullough and others, J NCI, Vol. 63, No. 3, September, p. 727-731 (1979) and R. L. Juliano et al., J. Ph. & Exp. Ther. , Voi. 214, No.2, pgs. 381 -387 (1980). A further report includes the use of cisplatin (M P = 300) for inhalation chemotherapy in mice that have been implanted with FM3A cells (cancer cells from murine mammals) in the air passages. It was reported that the inhalation group exposed to cisplatin had statistically smaller lung sizes and survived more than the untreated control group. See A. Kinoshita, "Investigation of Cisplatin Inhalation Chemotherapy Effeets on Mice after Air Passage Implantation of FM3A Cells", J. Jap. Soc. Cancer Ther. 28 (4): pgs. 705-715 (1993). In the patent of E. U.A. 5, 531, 219 of Rosenberg, the patent description suggests the use of doxorubicin, 5-FU, vinblastine sulfate or methotrexate in combination with liquid infused pulmonary fluorocarbons. It is suggested that the patient be positioned so that the affected area of the tumor is at a gravitational low point so that the liquid perfluorocarbon has relatively low vapor pressure will selectively combine around the area with the drug when perfused in the combination of liquid perfluorocarbon. The present invention avoids problems with patient positioning and furthermore does not require the liquid fluorocarbons used by Rosenberg. In the Patent of E. U.A. No. 5,439,686 to Desai et al., compositions are described wherein a pharmaceutically active agent is enclosed within a polymeric shell for administration to a patient. One of the administration routes listed as possible for the compositions of the invention is inhalation. Among the pharmaceutically active agents listed as potentially useful in the invention are anticancer agents such as paclitaxel and doxorubicin. It seems that no tests were done using the inhalation route of administration. Although several antineoplastic drugs have been administered to animals and humans, for the treatment of tumors in the lungs and the respiratory system, differences in the mechanism of action and toxicity profiles between the broad classes of anti-carcinogenic drugs and , therefore, known characterizations, it has become impossible to predict whether a particular anticancer drug will be effective or toxic based on the previous inhalation results with a different drug of a different type. In addition, the previous reports used very imprecise means to administer drugs and did not agree with the supply of measured doses of drugs in a uniformly distributed form to the entire respiratory tract. The present invention provides a means to predict and select drugs including highly toxic chemotherapeutic compounds willing to accept neoplastic disease inhalation therapy and methods for real-time delivery of specific metered doses to pre-selected regions of the respiratory tract. At the time, applicants have shown that multi-class anti-carcinogenic cytotoxic drugs such as anthracyclines (doxorubicin), antimicrotubular agents such as vinca alkaloids (vincristine) and taxanes such as paclitaxel can be given directly by inhalation without causing severe toxicity to the lung or other organs of the body. This finding is surprising, given that it is well known among those who administer cytotoxins such as doxorubicin to patients, that this drug causes severe ulceration of the skin and underlying tissues if it is allowed to be delivered outside of a vein. After extravasation the drug continues to affect the tissues so that an extension of the amputation of the limbs in which extravasation has occurred has been required. This toxicity is so severe that the information to prescribe doxorubicin (and some other similar vesication drugs) in the Physicians Desk Reference contains an "Alert Box" regarding this hazard. The present invention, therefore, provides an effective way to administer chemotherapeutic agents, including highly toxic agents such as doxorubicin, while minimizing the major side effects described above. BRIEF DESCRIPTION OF THE INVENTION Broadly, one embodiment of the invention includes a formulation for treating a patient for an inhaled neoplasm comprising: a safe and effective amount of a vesicant and a pharmaceutically acceptable carrier, preferably the vesicant exhibits no pulmonary toxicity substantial In one aspect of the modality, the vesicant is usually a moderate vesicant such as paclitaxel or carboplatin. A description of a moderate vesicant could include a non-encapsulated anti-carcinogenic drug, wherein when 0.2 ml of the drug is injected intradermally into the rats, at the clinical concentration for parenteral use in humans: (a) it results in a lesion that less is 20 mm2 in area, fourteen days after intradermal injection; and (b) at least 50% of the rats tested have this injury size. Other aspects of this wide variety typically include a vesicant that is a severe vesicant such as doxorubicin, vincristine and vinorelbine. The neoplasm that will normally be treated is a pulmonary neoplasm, a neoplasm of the head and neck or another systemic neoplasm. The drug may be in the form of a liquid, a powder, a liquid aerosol or a powder aerosol. Normally, the patient is a mammal such as a pet or a human being. In other aspects the embodiment includes formulations of drugs such as etoposide and a vehicle such as DMA. Typically, the severe vesicant is an anthracycline such as epirubicin, daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin, or iradubicin; or a vinca alkaloid such as vincristine, vinorelbine, vinorelbine, vindesine or vinblastine. In other formulations, the drug is usually mechlorethamine, mithramycin, dactinomycin, bisantrene or amsacrine. Typically, the formulation may include a taxane such as paclitaxel, its derivatives and the like. Normal animal and human doses are provided in the following tables. A further, extensive embodiment of the invention includes a formulation for treating a patient having a neoplasm by inhalation comprising: a safe and efficient amount of an unencapsulated antineoplastic drug having a molecular weight above 350, which does not exhibit lung toxicity substance! and an effective amount of a pharmaceutically acceptable vehicle. The neoplasm treated with the formulation is usually a pulmonary neoplasm, a neoplasm of the head or neck or a systemic neoplasm. The drug used in the formulation has the form of a liquid, a powder, a liquid aerosol or a powder aerosol. Normally the drug has a binding affinity to the protein of 25% or 50% or more. In addition, the drug can usually have higher molecular weights such as more than 400, 450 or 500 daltons. Normal animal and human doses are provided in the following tables and text. In still another embodiment of the invention, there is disclosed a formulation for treating a patient for an inhaled neoplasm comprising: a safe and effective amount of a taxane in an effective amount of vehicle comprising polyethylene glycol (PEG) and an alcohol. Normally the formulation will also contain an acid, wherein the acid is present in an amount effective to stabilize the taxane. Usually the alcohol is ethanol and the acid is an inorganic acid such as HCl, or an organic acid such as citric acid and the like. In some standard formulations, the taxane is paclitaxel and the formulation contains from about 8% to 40% polyethylene glycol, from about 90% to 60% alcohol and from about 0.01% to 2% acid. The normal doses of animals and humans are provided in the following table and texts.

Another embodiment provides formulations for treating a patient for a neoplasm by inhalation comprising: a safe and effective amount of a drug selected from the group consisting of carmustine, dacarbazine, melphalan, mercatopurine, mitoxantrone, esorubicin, teniposide, aclacinomycin, plicamycin, streptozocin and menogarilo; and a safe and effective amount of a pharmaceutically active vehicle, wherein the drugs do not exhibit substantial lung toxicity. An additional embodiment provides a formulation for treating a patient for a neoplasm by inhalation comprising: a safe and effective amount of a drug selected from the group consisting of estramustine phosphate, geldanamycin, briostatin, suramin, carboxyamido-triazoles; onconase and SU 101 and its active metabolite SU20; and a safe and effective amount of a pharmaceutically active vehicle, wherein the drugs do not exhibit substantial lung toxicity. A still further embodiment provides a formulation for treating a patient for an inhaled neoplasm comprising: a safe and effective amount of etoposide and an effective amount of a DMA vehicle. The normal doses of animals and humans are provided in the following tables and text. Another embodiment includes a formulation for treating a patient for a neoplasm by inhalation comprising: a safe and effective amount of a microsuspension of 9-aminocampotcin in an aqueous vehicle. The normal doses of animals and humans are provided in the following tables and text. A further broad embodiment of the invention includes a formulation for treating a patient having a neoplasm comprising: administering to the patient by inhalation, (1) an effective amount of a highly toxic antineoplastic drug; and (2) an effective amount of a chemoprotective agent, wherein the chemoprevent reduces or eliminates the toxic effects in the patient that are a result of the administration of a highly toxic antineoplastic drug. Normally the chemoprevent reduces or eliminates the systemic toxicity in the patient and / or reduces or eliminates the toxicity of the respiratory tract in the patient. Typically, the formulation includes a chemoprotectant such as dexrazoxane (ICRF-187), mesna (ORG-2766), etiofos (WR2721) or a mixture thereof. A chemoprevent can be administered before, after, or during the administration of the antineoplastic drug. An antineoplastic drug used with the chemoprotector may be non-vesicant, moderate vesicant or a severe vesicant. The normal drugs among the drugs with which the chemoprotector is useful are bleomycin, doxorubicin and mitomycin-C. The invention also usually includes a method for treating a patient having a neoplasm comprising: administering to the patient by inhalation, (1) an effective amount of a highly toxic antineoplastic drug; and (2) an effective amount of a chemopreventive agent, wherein the chemoprevent reduces or eliminates the toxic effects in the patient that result from the administration of the highly toxic antineoplastic drug. Normally the chemoprevent reduces or eliminates the systemic toxicity in the patient and / or reduces or eliminates the toxicity of the respiratory tract in the patient. The chemoprotectants can usually be dexrazoxane (ICRF-1 87), mesna (ORG-2766), etiofos (WR2721) or a mixture thereof. The chemoprotectant can be administered before, after, or during the administration of an antineoplastic drug. Normally the antineoplastic drug is a non-vesicant, a moderate vesicant or a severe vesicant. Normally the antineoplastic drug comprises bleomycin, doxorubicin or mitomycin-C. A further embodiment of the invention includes a method of treating a patient having a neoplasm comprising: administering a safe and effective amount of a non-encapsulated antineoplastic drug to the patient by inhalation, the drug selected from the group consisting of antineoplastic drugs wherein when 0.2 ml of the drug is injected intradermally in rats, at the clinical concentration for IV use in humans: (a) at least one lesion per rat results which is greater than an area of 20 mm2 fourteen days after the injection intradermal; and (b) at least 50% of the rats tested have these lesions. In some normal modalities when the drug is doxorubicin or vinblastine sulfate, the drug is inhaled in the absence of perfluorocarbon. Normal diseases treated include a neoplasm such as a pulmonary neoplasm, a neoplasm of the head and neck or other systemic neoplasm. The drug can normally be inhaled as it is inhaled as a liquid aerosol or as a powdered aerosol. Mammalian animals and humans are normal patients treated with the method. The drug can normally be selected from the group consisting of doxorubicin, daunorubicin, methoxymorpholino-doxorubicin, epirubicin, cyanomorpholinyl, doxorubicin and idarubicin. When the drug is an alkaloid vinca it is usually selected from the group consisting of vincristine, vinorelbine, vindesine and vinblastine. Other useful drugs typically include the alkylating agents, mechlorotamine, mithramycin, and dactinomycin. Even the additional useful drugs typically include bisantrene and amsacrine. The drug can normally be a taxane such as doxitaxel or paclitaxel. Another embodiment of the invention includes a method for treating a patient having a neoplasm comprising: administering an effective amount of a highly toxic non-encapsulated antineoplastic drug to a patient by inhalation, wherein the molecular weight of the drug is above 350, and the drug does not have substantial pulmonary toxicity. Normally the neoplasm is a pulmonary neoplasm, a neoplasm of the head and neck or a systemic neoplasm. The drug can be inhaled as a liquid aerosol or as a powder aerosol. Normally, the drug has a protein binding affinity of 25%, 50% or more. In one aspect, the drug is usually selected from the group comprising doxorubicin, epirubicin, daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl, doxorubicin and doxorubicin. If the drug is doxorubicin or vinca alkaloid, it can usually be administered without the presence of a perfluorocarbon. Normally the alkaloid vinca is selected from the group consisting of vincristine, vinorelbine, vindesine and vinblastine. Normal drugs of the alkylating agent type include mechlorotamine, mithramycin, dactinomycin. Other inhibitors of topoisomerase I I include bisantrene or amsacrine. A further embodiment includes a method of treating a patient for a neoplasm by the steps of administering an effective amount of an antineoplastic drug to the patient by inhalation; and administering a pharmaceutically effective amount of the same and / or different antineoplastic drug to the patient parenterally. The patient can be treated with one or more adjunct therapies including radiation therapy, immunotherapy, gene therapy, chemoprotective drug therapy. A further embodiment includes a method for treating a patient for a neoplasm including the steps of administering an effective amount of an antineoplastic drug to the patient by inhalation; and administering an effective amount of the same antineoplastic drug and / or different to the patient by perfusion of isolated organs. The patient can be treated with one or more adjunct therapies including radiation therapy, immunotherapy, gene therapy, chemoprotective drug therapy. A further embodiment, includes a method for treating a patient for a pulmonary neoplasm by the steps of (1) selecting one or more effective antineoplastic drugs to treat the neoplasm and having a sufficient residence time in the pulmonary mucosa to be effective in the treatment of the pulmonary neoplasm; and (2) administer the drugs to the patient by inhalation in an unencapsulated form. Normally when 0.2 ml of at least one of the drugs is injected intradermally into rats, at the clinical concentration for parenteral use in humans: a lesion is greater than 20 mm2 area, fourteen days after the intradermal injection; and B. at least 50% of the rats tested have these lesions. Normally the molecular weight of at least one of the selected drugs is about 350. A still further embodiment includes a method of use including steps for administering one or more highly toxic anti-cancer drugs not encapsulated to a mammal by inhalation, wherein at least one of the drugs comprises a severe vesicant. Another embodiment is an apparatus for treating a patient against a neoplasm by inhalation, which is in combination with a nebulizer and a formulation for treating a neoplasm, the formulation including (1) a non-encapsulated anti-cancer drug and ( 2) a pharmaceutically acceptable vehicle; wherein when 0.2 ml of the formulation is injected intradermally into rats, at the clinical concentration for parenteral use in humans: (a) results in a lesion that is greater than about 20 mm2 area, fourteen days after the intradermal injection; and (b) at least 50% of the rats tested have these lesions. An additional embodiment includes the formulation which when injected results in a lesion that is greater than about 10 mm2 in area, 30 days after the intradermal injection; and at least about 50% of the rats tested have these lasting injuries. Normally the formulation includes an anthracycline. The anthracyclines can be selected from the group consisting of epirubicin, daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin and idarubicin. The formulation normally also contains an alkaloid vinca. Vinca alkaloids can be selected from the group consisting of vincristine, vinorelbine, vinorelbine, vindesine and vinblastine. Alternatively, the formulation may contain vesicant selected from the group consisting of mechlorotamine, mithramycin and dactinomycin; or bisantrene or amsacrine. Typically, the formulation may also contain a taxane which is usually paclitaxel or doxitaxel. Another embodiment of the invention includes an inhalation mask for administering aerosols to a patient comprising: means for covering the mouth and nose of the patient, having an open end and a closed end, the open end adapted to be placed over the mouth and nose of the patient. patient; the upper and lower holes at the closed end adapted for the 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 patient's nose; a one-way valve in the nose tube adapted to allow exhalation but not inhalation; the inhalation tube of the mouth having an outer end and an inner end, partially inserted through the lower hole, the inner end continuing to the end of the back of the patient's mouth, the end of the inhalation tube cut into a angle so that the lower portion extends more into the patient's mouth than the upper portion and adapts to conform to the curvature of the back of the patient's mouth; and an adapter in the form of and attached to the outer end of the mouth inhalation tube. The mask will usually have a moderate vesicant or severe vesicant present in the inhalation tube. BRIEF DESCRIPTION OF THE DIAMETERS Figure 1 shows a plasma drug concentration time profile for dog # 101 having been administered intravenously doxorubicin (IV) (circles) and the inhalation route pul monar (IH) (squares) ). The vertical Y scale is the concentration of the drug in the circulatory system in ng / ml and the scale in horizontal X is the time after the treatment in hours. Figure 2 shows a time profile of drug concentration of the plasma for dog # 102 having been administered intravenously doxorubicin (IV) (circles) and lung inhalation route (IH) (squares). The vertical Y scale is the concentration of the drug in the circulatory system in ng / ml and the scale in horizontal X is the time after the treatment in hours. Figure 3, shows a time profile of plasma drug concentration for dog # 103 having been administered intravenously doxorubicin (IV) (circles) and lung inhalation route (IH) (squares). The vertical Y scale is the concentration of the drug in the circulatory system in ng / ml and the scale in horizontal X is the time after the treatment in hours. Figure 4 shows a diagram of the disposition of the pulmonary delivery apparatus that was used to administer drugs to dogs by inhalation for example 3. Figure 5 shows a diagram of the disposition of the pulmonary delivery apparatus 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 the details of the masks useful for administering drugs by inhalation to a mammal such as a dog.

Figure 7 shows a schematic drawing and a portable device for the administration of anti-carcinogenic drugs according to the invention. DETAILED DESCRIPTION OF THE NONDION AND BETTER WAY The supply of antineoplastic drugs by inhalation through the pulmonary route is an attractive alternative for the administration of drugs by various injectable methods, particularly those drugs that occur in a chronic or repeated administration program. A cause for concern is the toxic nature of the drugs, particularly those that are cytotoxic such as those represented by classes represented by alkylating agents, taxanes, vinca alkaloids, platinum complexes, anthracyclines and others that are considered particularly toxic especially when administered outside the circulatory system. Broadly, the inventors have discovered that the highly toxic vesicant and non-vesicant antineoplastic drugs previously unknown can be effectively delivered to a patient in need of the treatment of neoplasms or cancers by inhalation. This route is particularly effective for the 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 the regional doses much higher than what can be achieved by conventional IV delivery. As used herein, the respiratory tract includes the oral and nasal-pharyngeal, tracheo-bronchial and pulmonary regions. The lung region is defined by including the upper and lower bronchi, bronchioles, terminal bronchioles, respiratory bronchioles and alveoli. An important benefit of inhalation therapy for neoplasms of the head and neck and respiratory tract is that exposure to the rest of the body is controlled after administration of high doses of the drug and consequently many of the adverse side effects associated with frequencies with high doses of highly toxic antineoplastic drugs administered systemically, even the significantly increasing doses are provided at the tumor site. These toxic effects include, for example: cardiac toxicity, myelosuppression, thrombocytopenia, renal toxicity and hepatic toxicity that are often life-threatening. The toxic effects are often so severe that it is not common for patients to die from the effects of the drugs administered systemically rather than by the disease for which they are being treated. Broadly, the vesicants as used herein, include chemotherapeutic agents that are toxic and normally cause long-term damage to surrounding tissue if the drug is extravasated. If inadvertently delivered outside a vein, a vesicant has the potential to cause pain, cell damage including cel ulitis, tissue destruction (necrosis) with the formation of a lasting lesion or ulcer and tissue scars that may be extensive and require grafting. of skin. In extreme cases of extravasation of vesicants such as doxorubicin has required the surgical removal of the affected area or amputation of the affected limb. Examples of antineoplastic chemotherapeutic agents that can be generally accepted vesicants include alkylating agents such as mechlorotamine, dactinomycin, mithramycin; inhibitors of topoisomerase I I such as bisantrene, doxorubicin (adriamycin), daunorubicin, dactinomycin, amsacrine, epirubicin, daunorubicin and idarubicin; tubulin inhibitors such as vincristine, vinblastine and vindesine; and estramustine. A partial list of vesicants are found in Table 1. In another embodiment, the vesicants that are used most closely in the present, they include drugs that produce a lesion in rats, where the size of the average lesion is greater than approximately 20 mm2 of area, fourteen days after an intradermal injection of 0.2 ml of the drug and where 50% or more of the animals they have this size of injury. The concentration of the drug for intradermal injection is the clinical concentration recommended by the manufacturer for use in humans, the recommended dose in Physicians Desk Reference, 1997 (or a more current version of this reference) or another drug handbook for health specialists . If there is no recommendation by the manufacturer (for example because the drug is new) and if there is no recommendation in Physicians Desk Reference or similar drug handbook for health specialists then another current medical literature can be used. If more than one clinical concentration is recommended, the highest recommended clinical concentration is used. The lesion, as used herein, means an open scar or ulcer or skin sores with exposure to the underlying tissue. In yet another embodiment of the invention, 0.2 ml of a highly toxic anti-carcinogenic drug (vesicant) at a dose recommended for humans (as discussed above), is administered intradermally to rats at a concentration that results in the size of the lesion. mentioned earlier for a longer time. That is, the lesions remain above 10 mm2 for at least 30 days and in at least 50% or more of the animals. Non-vesicants usually also irritate and can cause pain, but usually do not result in lasting scars or ulcers or tissue scabs except in rare cases. Examples include alkylating agents such as cyclophosphamide, bleomycin (blenoxane), carmustine and dacarbazine; DNA entanglement agents such as thiotepa, cisplatin, melphalan (L-PAM); antimetabolites such as cytarabine, fluorouracil (5-FU), methotrexate (MTX) and mercaptupurine (6 MP); inhibitors of topoisomerase I I such as mitoxantrone; epipodophyllotoxins such as etoposide (VP-16) and teniposide (VM-26); hormonal agents such as estrogens, lucocorticosteroids, progestins and antiestrogens; and various agents such as asparaginase and streptozocin. A list of materials usually accepted to be vesicant or non-vesicant is provided below as Table 1 - Activity of Vesicant / Non-Vesicant Drugs. Table 1 Activity of Vesicant / Non-Vesicant Drugs a - According to the Patent of E.U.A. No. 5,602,112 b - Dorr, R.T. and others, Lack of Experimental Vesicant Activity for the Anticancer Agents Cisplatin, Melphalan, and Mitoxantrone, Cancer Chemother. Pharmacol., Vol. 16, 1986, pp. 91-94 c - According to Bicher, A. and others, Infusion Site Soft-Tissue Injury After Paclitaxel Administration, Cancer, Vo. 76, No. 01 July 1995, p. 116-120 d - Rudolph, R. and others; Etiology and Treatment of Chemotherapeutic Agent Extravasation Injuries: A Review; Journal of Clinical Oncology; Vol. 5; No. 7; July 1987; p. 1116-1126 e-Bertelli, G., Prevention and Management of Extravasation of Cytotoxic Drugs, Drug Safety, 12 (4) 1995; p. 245-255. The listed drugs have been reported in at least one case, either clinically or experimentally, for causing tissue necrosis after accidental extravasation. Symbol: * = vesicants, drugs with the highest potential for localized tissue damage after extravasation. f - Cancer, R.T., Communications, Author Reply, Cancer, p. 226 Normal embodiments of the invention use highly toxic antineoplastic drugs that have vesicant activity similar or greater than those that have been tested on animals by inhalation to date. One modality typically uses severely vesicant highly toxic antineoplastic drugs that have superior vesicant activity than those represented by 5-FU, β-cytosine arabinoside (Ara-C, citrabine), mitomycin C, and cisplatin. With respect to the latter, it is described that a highly toxic drug represented by the classes of anthracyclines (of which doxorubicin is among the most toxic), has been administered by inhalation to a patient in need of treatment of neoplasms. In a further embodiment of the invention, it is described that vesicants other than doxorubicin can be given to patients by inhalation. With respect to the latter, the highly toxic drugs represented by the vinca alkaloid and taxane classes, which have similar high toxicities, have been administered by inhalation to a patient in need of treatment of neoplasms. In still a further embodiment of the invention, it is described that certain antineoplastic drugs that are not vesicants can be administered by inhalation to a patient in need of treatment for neoplasms. In a further embodiment of the invention, formulations and methods are described for applying the highly toxic drugs mentioned above to a patient in need of treatment for pulmonary neoplasms by halazing.

Example 1 This example illustrates and confirms the toxicity and vesicant / non-vesicant activity of various antineoplastic drugs. The vesicant activities of thirteen anti-carcinogenic drugs were investigated (see the list in Table 2 below). Doxorubicin has traditionally been considered a vesicant (see Table 1). Paclitaxel had previously been considered a non-vesicant, but in recent literature its classification as a vesicant has been evoked. Some of the remaining drugs are traditionally considered as vesicants and other non-vesicants (Table 1). The fourteenth day after the injection was chosen as the time for the comparison of vesicant activity, because the lesions caused by the non-vesicants could have been significantly reduced while the lesions caused by the vesicants could become larger. Sterile saline solution (0.9%) for USP injection, pH 4.5-7.0, or sterile water for injection, as appropriate, was used to reconstitute the drugs. The drugs used for vesicant activity tests were identified as follows: doxorubicin (Adriamycin PFS), a red liquid in glass ampules, no formulation was necessary; cisplatin (Platinol-AQ ™), a liquid in glass ampoules, no formulation was necessary; Paclitaxel (Taxol ™), a liquid in ampoules, formulated with saline; fluorouracil, a yellow liquid transient in glass ampoules, the formulation was not necessary; cytarabine (Cytosar-U ™), a white powder in glass ampules, formulated with water; 9-aminocampotcin (colloidal suspension 9-AC), a yellow powder in glass ampoule, formulated with water, cyclophosphamide (Cytoxan ™), a yellow powder in glass ampules, formulated with a mixture of saline / water; carboplatin (Paraplatin ™), a white powder in injectable vials, formulated with saline; etoposide (VePesid ™), a clear liquid in glass ampoules, formulated with saline; bleomycin (bleomycin sulfate, USP), a lyophilized powder tablet in glass ampules, formulated with saline; vincristine (vincristine sulfate), an injectable liquid in injection ampoules, the formulation was not necessary; vinorelbine tartrate (Navelbina ™), a clear liquid in glass ampules, diluted with water with packaging instructions; and mitomycin (Mutamycin ™), a gray crystalline powder in amber glass bottles, formulated with water. All these drugs were reconstituted after normal and known methods recommended by the manufacturers. Vesicant activity tests were carried out using Sprague Dawley rats (7-8 weeks of age having 150-200 g of body weight), each receiving a single transdermal injection of the test drug and the recommended clinical concentration (listed below). forward in Table 2) on the right back Approximately 24 hours before administration, the hair was removed from the back using forceps and a depilatory agent.

Each 0.2 ml of injection was injected with a 1 ml syringe and a 27 gauge needle. All drug solutions were isotonic or slightly hypertonic. Table 2 Formulations administered for Vesicant tests Table 3 below is a tabulation of the resulting lesion sizes that are developed by intradermal injections of the above drugs. Injury sizes were measured as discussed more fully below.

Table 3 (continued, part 2 of 3) ? Table 3 (continued, part 3 of 3) co in The results are the following: 1. Abrasions of the dorsal body were observed in most animals for all drugs except cytarabine. 2. Alopecia of the dorsal body was observed for doxorubicin (3/7), paclitaxel (7/7) and fluorouracil (7/7), etoposide (7/7), bleomycin (7/7), vincristine (2/7), vinorelbine (7/7) and mitomycin-C (mutamycin) (4/7). 3. Skin discoloration was observed around the injection site for doxorubicin, vincristine, vinorelbine and mitomycin-C. 4. Rough cover was observed in fluorouracil (1/7), vincristine (4/7) and vinorelbine (2/7). 5. Systemic effects were observed only for vincristine. Three animals had to be removed from the tests due to their poor condition. 6. Light edema was observed for all groups. Moderate edema was observed in animals treated with doxorubicin, vincristine, vinorelbine and mitomycin-C. Severe edema was observed only for animals treated with vinorelvin and vincristine. 7. Severe erythema was observed for all drugs except for cisplatin (platinol) and cytarabine. 8. Dermal lesions were observed for all drugs except cytarabine. Most lesions appeared between days 6 and 10 and increased in size during the first seven days and then gradually decreased in size. Doxorubicin, vincristine, vinorelbine and mitomycin C, were the only drugs that caused lesions that took up to 10 months. Term of the test on day 41. However, for mitomycin-C only one animal of seven still had injuries at the end of the test. It was determined that a rat (# 123) injected with paclitaxel (taxol) had not received an appropriate intradermal injection and was not used in the results. It was determined that dermal lesions at the injection site are the best and most objective measures and predict vesicant activity for a drug. The size of the lesion was quantified by micrometer measurements of. the two largest perpendicular diameters and the two values multiplied to give an area of injury in mm2. The lesions were regularly evaluated and classified as shown in Table 3. By the methods used herein, it was determined that a vesicant is defined as causing a lesion of at least about 20 mm2, in at least half of the animals, two weeks after the injection (day 15 in Table 3). Table 3 shows that doxorubicin, paclitaxel, carboplatin, vincristine, vinorelbine and mitomycin-C meet this criterion. Cisplatin, etoposide, bleomycin, cytarabine, cyclophosphamide, fluorouracil, and 9-aminocampotcin are categorized as non-vesicants. By the methods used herein, it was determined that a moderate vesicant is defined as causing a lesion of at least about 20 mm2, in at least half of the animals, two weeks after the injection (day 15 in the Table). 3), but less than half of the animals will have lesions greater than about 10 mm2 30 days after the injection (day 31 in Table 3). The data in Table 3 show that paclitaxel, carboplatin and mitomycin-C meet these criteria. Of these, it was determined that mitomycin-C exhibits substantial lung toxicity. By the methods used herein, it was determined that a severe vesicant is defined as causing a lesion of at least 2 mm2, in at least half of the animals, two weeks after the injection (day 15 in Table 3) and at least half of the animals will still have lesions greater than approximately 10 mm2, 30 days after the injection ( day 31 in Table 3). Table 3 shows that doxorubicin, vincristine and vinorelbine meet these criteria. Surprisingly, it has been found that moderate to severe vesicants can be used for cancer inhalation therapy as disclosed in the discussion and following examples. In addition, it has also been found that other highly toxic drugs, although not having the reaction severity of moderate to severe vesicants, are useful in the treatment of cancer by inhalation as discussed below. Antineoplastic drugs that are highly toxic and useful in a manner of the present invention, include the anthracyclines (eg, doxorubicin, epurubicin, idaru bicin, methoxymorpholinodoxorubicin, daunorubicin, and the like).; vinca alkaloids (e.g., vincristine, vinblastine, vindesine and the like); alkylating agents (e.g., mechlorotamine and the like); carboplatin; nitrogen mustard (e.g., melphalan and the like), topoisomerase I inhibitors (eg, 9-aminecampotcin, campotcin, topotecan, renothecan, 9-NO-campotcin and the like); inhibitors of topoisomerase I I (e.g., etoposide, teniposide and the like); and paclitaxel and the like. These and other useful compounds are discussed below. In yet another embodiment of the invention, formulations and methods are described for applying an appropriate selection of highly toxic drugs that are effective in treating the neoplasm or cancer, which are applied by inhalation and reside in the pulmonary system for a sufficient time to increase the exposure of the neoplasm to the drug, still allow a reduction and / or a controlled systemic exposure of the drug, and provide a more effective treatment for pulmonary neoplasms. In a further embodiment of the invention, it is disclosed that it is possible to deliver antineoplastic drugs through the pulmonary route as a means to provide systemic treatment of distant tumors. The inventors have shown that for the inhalation of selected drugs a non-invasive route can be used to be delivered without causing significant toxicity to the respiratory tract. This is in contrast to the prior art which uses inhalation for treatment of disease in the respiratory system. As used herein, the term "patient" encompasses a mammal that includes, but is not limited to, mice, rats, cats, horses, dogs, cattle, sheep, apes, monkeys, goats, camels, other domesticated animals and humans in progress. Administration by inhalation as used herein includes respiratory administration of the drug as liquid aerosols or aerosol powders suspended in a gas such as air or other non-reactive vehicle gas that is inhaled by a patient. The non-encapsulated drug as used herein means that the antineoplastic drug is not enclosed within a liposome, or within a polymer matrix or within a closed envelope. When the encapsulated thermal drug is used herein, the term means that the antineoplastic drug is enclosed within a liposome, within a polymeric matrix or within a closed envelope. However, in some embodiments the anti-neoplastic drug can be coupled to several molecules even if it is not enclosed in a liposome, matrix or shell as discussed below. In other embodiments of the invention, the antineoplastic drugs described herein, can be coupled with other molecules through ester ligatures. The enzymes present in the respiratory system then separate the ester bonds. A purpose for coupling the antineoplastic drugs through an ester ligation is to increase the residence time of the antineoplastic drug in the pulmonary system. The increased residence time was achieved by: first, an increase in molecular weight due to the bound molecule; second, by an 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 deposit area of the active drug in the respiratory tract. As a demonstration of proof of concept, doxorubicin was used in a series of tests. Doxorubicin was chosen as an initial test agent since it is one of the most cytotoxic and potent vesicants of all anti-neoplastic agents considered in the broad modality (pulmonary delivery of anti-neoplastic drugs) of the present invention. Based on the positive production of these proof-of-concept studies, anti-carcinogenic drugs of other major classes were tested simultaneously. The results consistently showed that using the approach and methods described in this invention, the drug could be safely and effectively delivered by inhalation. In the following Examples 2 and 3, doxorubicin was administered to three dogs (beagle) by pulmonary and intravenous route of administration. The dogs were given a clinically effective dose of the drug and the amount of the drug that appeared in the blood system was measured. An anthracycline antineoplastic drug, a doxorubicin salt, doxorubicin HCl, available from Farmitalia Cario Erba (now Fharmacia & amp;; U pjohn), Milan, Italy, was used in some of the present examples. The liquid formulation that was administered to the dogs was by inhalation of an aerosol was obtained by mixing doxorubicin hydrochloride with a mixture of ethanol / water at a doxorubicin concentration of approximately 15-25 mg / ml. Solutions of 5 to 75% ethanol are usually preferred. The water / ethanol ratios can be adjusted to select the desired concentration of doxorubicin and the desired particle size of the aerosol. Example 2 Three dogs, beagle, males, adults, were used in these tests. Dogs (designated dogs 101, 102 and 103) had body weights of 10.66, 10.24 and 10.02 kg, respectively, as used in the present "m2" used only with reference to dose refers to square meters in terms of surface area body of an animal or patient treated, at another time it was graded in terms of area of its lung surface. Dogs were given a slow iv infusion treatment of the anthracycline drug HCl of doxorubicin at the recommended initial clinical dose (for dogs) of 20 mg / m2 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 ratio of the inhalation group in the following Example 3. A series of blood samples were taken to characterize IV pharmacokinetics at previous doses of 2, 5, 10, 30 , 60, 90 minutes and 2, 4, 6, 12, 18 and 36 hours after dosing. Additional blood samples were recovered by clinical pathological evaluations on days 3 and 7 of IV treatment. The changes in blood chemistry and hematology were as expected with the administration of doxorubicin HCl at these doses. Example 3 To the three dogs used in Example 2, they were left an unwashed period of one week before being exposed to the anthracycline drug of doxorubicin HCl by inhalation. The dogs were acclimated to use masks for aerosol administration before treatment. The dogs were exposed to an aerosol concentration of the drug sufficient to deposit a total dose of approximately 10 mg (1 mg / kg). Based on aerosol dosimetry models, approximately half of that dose was deposited within the respiratory tract. The total dose was approximately equal to the dose administered by IV infusion. The dose was calculated using the following equation: Dosage =. { Concentration of the drug (mg / liter) x Average volume in minutes (liter / min.) X Duration of exposure (min.) X Fraction of Total deposit (%)} -s- Body Weight (kg) where Average Volume in minutes = Respiratory rate of flow volume x minute Exposure Duration 30 minutes Body Weight Medium weight in kg for each dog Fraction of Total Deposit 60% (determined by the models of the Respiratory tract particle and reservoir size from published literature such as "Respiratory Tract Deposition of I nhaled Polydisperse Aerosols in Beagle Dogs", R. G. Cuddihy et al., Aerosol Science, Vol 4, pp. 35-45 (1973) ) and "Deposition and Retention Models for Internal Dosimetry of the Human Respiratory Tract", Task Group on Lung Dynamics, Health Physics, Vol. 12, pp. 173-207 (1966), Pulmonary Function Measurements (Respiratory Regimen, Volume of flow and volume in minutes (calculated)) were monitored during a 30-minute inhalation exposure session.These data provided a calculation of each volume of animal inspiration and were used to calculate the mass of the drug deposited. itate in the respiratory tract. A series of blood samples were recovered at the end of the exposure to characterize the pharmacokinetics. The clinical pathology evaluations were carried out on the third day. The 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 the 400 drug exposure system. The drug was sprayed with two Pari LC Jet Plus ™ 401 nebulizers. The nebulizer was filled with a 15 mg solution of doxorubicin per ml of 50% water / 50% ethanol. The output of each nebulizer 401 was continuous and provided the required concentration of aerosol in the connected plenum 405. The nebulizers 401 were directly connected to the plenum 405 which has a volume of approximately 90 liters. The plenum 405 was connected by four tubes 407 to four venturi tubes 409, respectively, and subsequently connected to four Y-fittings 413 by additional pipe 41 1. Normal venturi tubes were used to measure the inhaled volume of the drug formulation. One end of each of the Y-shaped fittings 41 1 was interspersed with a dog breathing mask 415 while the other end of the Y-fitting 41 1 was connected to a pipe 417 leading to an exhaust pump 419 During the tests, the three dogs 41 8 were adapted with three breathing masks 415. A recovery filter 421 was placed in the remaining mask 41 5. A vacuum pump 423 was used that extracted 1 liter per minute of air for 3 minutes instead of a dog to extract aerosol in order to monitor and measure the amount of the drug administered. The vacuum pump was activated four times during the 30 minute administration of the drug to the dogs and the amount of the drug trapped by the filter is shown in the following Table 5. An air flow was supplied to each of the nebulizers 401 of a supply of air 425 via lines 427. Additional air to provide an air flow through the system and for the respiration requirements of the dogs was provided from the air supply 425 by the 429 supply lines connected to one-way valves 431. One-way valves 431 were connected to the upper portion of nebulizers 401. This additional air supply provided a continuous flow of air through system 400 from air supply 425 to the pump. Exhaust 417. Alternatively, the extra supply of air can be eliminated from the supply lines 429 to one way valve 421 and allowed to enter the air at room temperature m the one-way valve of the suction action of the nebulizers 401. A Hepa 441 filter mounted to the top of the full 405 allowed the air from the room to flow in and out of the full 405 and ensuring that there would always be environmental pressure in the plenary. There was continuous flow of air containing the aerosol after the masks of the dogs and the dogs were able to breathe the air containing the spray on demand. An inner tube 621 located inside the dog's respiration mask 415 was spread in the mouth of the dogs and was provided with an extension 633 to its lower portion which served to press the tongue of the dogs in order to provide a respiratory route. open to breathe. See the discussion in Figure 6 below. Each of the four venturi tubes 409 was connected via line 441 to a pressure transducer 443 (the one shown is normal for the four venturi tubes) which was used to measure pressure differences across the venturi. The pressure transducers 443 were connected via line 445 to an analog amplifier 447 to increase the output signal and prepare the signal sent via line 449 to the computer system 451. The 451 computer system is a class of desktop PC model of standard design in the industry and can be used in conjunction with a software program BUXCO or PO-N E-MAH to calculate the air absorption containing aerosol and thus the dose of drug for each of the dogs. The following Table 4 summarizes the exposure data for the administration of doxorubicin for dogs from Example 3. The total mass of each dog was determined. The total inhaled volume of air during the 30 minutes of drug administration was measured in liters. The concentration of aerosol in mg of drug / liter of air (mg / l) was determined by calibration tests carried out before. A total deposit fraction of 60% was calculated (as calculated 30% of the inhaled dose was deposited in the upper respiratory tract and the peripheral lung while an additional 30% was deposited in the oral-pharyngeal region) based on the size of aerosol particles of doxorubicin measured and literature published (see references cited above).

Therefore, about 25% -30% of the administered doxorubicin was deposited and was available for the lung region. Since the drug was administered in its salt form, a correction was made for the chlorine portion of the molecule. As shown in Table 4, this resulted in an applied dose of 0.51, 0.60 and 0.57 mg / kg to the lung region of dogs 101, 102 and 103, respectively. The filter data obtained from the drug analysis deposited on the filter 421 placed in a fourth mask 415 are shown in Table 5 for four different measurements. The mass of drug recovered in the filter was corrected for the chlorine portion of the doxorubicin salt. Finally, the concentration of doxorubicin in the three liters of air extracted in each mask was determined in mg / l. The four figures were averaged to obtain a mean doxorubicin aerosol concentration of 0.218 mg / l. Table 6 shows the data and calculations that verify the figures in Table 4. I weight of the dog and the respiration volumes measured for Table 4 were used. However, the average concentration of doxorubicin that was obtained from the filter data shown in Table 5 was used to calculate doxorubicin concentrations. Calculating the data as in Table 4, the dose inhaled for each dog was calculated. The inhaled dose was reduced by 40% as before to obtain the total dose deposited and reduce by 50% again to obtain the total lung dose deposited. The lung doses obtained by this method of 0.47, 056 and 0.53 mg / kg for dogs 101, 102 and 103 were respectively compared with the figures calculated earlier in Table 4.

TABLE 4. TOTAL MASS DATA Total Vol. Inhaled Conc. (I) Dosage Fractional Dose Dosage Dose Weight for 30 Inhaled Air Fraction Art. Inhaled Pulmonary Deposit Dog No. Dog (kg) Min. (Mg / l) Tank Test (mg / kg) (mg) kg) (mg / kg) 101 10.66 77.5 0.250 0.60 0.937 1.70 1.02 0.51 102 10.24 86.8 0.250 0.60 0.937 1.99 1.19 0.60 103 10.02 80.8 0.250 0.60 0.937 1.89 1.13 0.57 ABCDE TABLE 5. FILTER DATA Vol. Of Mass of Conc. Of Sample Shows Gain on doxorubicin Conc. Total Doxorubicin Ratio of No. (liter) Weight (mg) (mg) (mg / l) (mg / l) DoxTotal 1 3 0.78X.937 0.70 0.260 0.233 0.897 2 3 0.72X.937 0.61 0.240 0.203 0.847 3 3 0.73X.937 0.62 0.243 0.207 0.849 n 4 3 0.77X.937 0.68 0.257 0.227 0.883 or Average 0.240 0.218 0.869 A B C D TABLE 6. ANALYTICAL DATA Dose Dose Dose Weight of Total Vol. Inhalation Concluded Pulmonary Deposit Dog No. Dog (kg) Inhaled (kg) Aerosol (mg / l) (mg / kg) (mg / kg) (mg / kg) ) 101 10.66 77.5 0.218 1.58 0.95 0.47 102 10.24 86.8 0.218 1.85 1.11 0.56 103 10.02 80.8 0.218 1.76 1.06 0.53 ABC Surprisingly it has been found that free non-encapsulated doxorubicin, administered via the pulmonary route, was not rapidly eliminated from the lung. Figures 1, 2 and 3 show examples of the type of results achieved when they are given by inhalation of cytotoxic anti-carcinogenic drugs. High efficiency nebulization systems, as shown in Figures 4 and 5, were used to deliver a large percentage of the drug sprayed to the lung region of the respiratory tract. Doses equal to or greater than those that cause IV toxicity were only moderately absorbed in the blood after pulmonary delivery and caused little or no direct or systemic toxicity after a single exposure to this dose. As can be seen from Figures 1, 2 and 3, doxorubicin administered by the pulmonary route achieved a consistently lower level of doxorubicin in the systemic blood, with peak blood levels above an origin of lower magnitude after the exposure to inhalation. The initial concentration of doxorubicin at 2 minutes was approximately 1.5 orders of magnitude larger than that administered IV than by the pulmonary route. At the last, after 4 hours, the systemic level of doxorubicin was approximately six times higher for the drug administered IV. This suggests that the free doxorubicin remained in the lung for an extended time and slowly passed through the mucosa in the systemic circulation this network uce the systemic toxic effects of the drug and allows its concentration in the lung for the most effective treatment of neoplasms associated with the respiratory tract while global systemic toxic effects are reduced. It is thought that the toxic effects of doxorubicin to the tissues outside the lung are the result of the high levels mentioned before the concentration of the systemic drug after IV treatment: Another surprising finding was that 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). As noted earlier, doxorubicin belongs to the anthracycline class of drugs that are normally very toxic. Doxorubicin is one of the most toxic drugs of this class, even though the dogs in the test were necropsied, no damage to the respiratory tract was observed. It is surprising that doxorubicin was not toxic to the lung when given by inhalation at clinically relevant doses such as 20 to 50 mg / m2. Unlike 5-FU and Ara-C and cisplatin, it is well known that doxorubicin generates the production of free radicals (Myers et al., 1977) that are notorious for causing pulmonary toxicity (Knight, 1995). In fact, this property is responsible for the cardiac toxicity caused by intravenous doxorubicin (Myers and others, 1977). In some normal embodiments, to obtain additional benefits of the disclosed invention to treat lung neoplasms and reduce systemic toxicity, it is important that antineoplastic drugs administered in the non-encapsulated form by the pulmonary route be absorbed into and remain in the lung tissue for a period of time. extended time and diffuse through the lung mucosa in a relatively slow manner. In general, although the solubility, charge and form have an influence, it is obtained by slow diffusion of the drugs having higher molecular weights while obtaining faster diffusion of those with relatively lower molecular weights. Therefore, drugs such as doxorubicin that have a molecular weight of 543.5, have relatively slow diffusion rates, drugs such as vincristine (MW = 825), vinblastine (MW = 81 1), paclitaxel (MP = 854). , etoposide (MW = 589), which have higher molecular weights also diffuse slowly, other drugs having somewhat lower molecular weights such as 9-aminocampotcin, although they diffuse more slowly are still included within the invention. It has been shown that significantly high tissue concentrations can be achieved in the lung by pulmonary delivery compared to conventional parenteral or oral administration. In addition, the systemic coverage of micrometastases can be improved under these conditions, with the benefit of significantly higher doses of the drug delivered to the tumor sites of the respiratory tract and controlled systemic exposure. Therefore, in one embodiment of the invention, drugs having a molecular weight greater than 350 are used. In this regard, mitomycin-C (MW of about 334) is excluded from this modality. While molecular weight is not the only determinant that will control diffusion through the lung, it is one of the important factors in selecting compounds useful in the present invention. This lower molecular weight limit is about 65% doxorubicin. This will help ensure that the limited systemic availability of the drug treated earlier is maintained. In additional embodiments of the invention the molecular weight of the administered drugs is above 400, 450 and 500, respectively. In conjunction with the molecular weights discussed above, protein binding of anti-neoplastic agents that will be delivered by pulmonary administration should also be considered with respect to diffusion through the lung. Higher rates of protein binding will also decrease diffusion through the lung mucosa. In this regard, 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 in a solution containing protein, only 7% and 13% of these drugs bind to the protein while the rest is free in the solution. In this respect, cisplatin does not bind to tissues, instead of a final stage is platinum in the cisplatin that binds to the tissues, thus allowing cisplatin to enter the systemic circulation as discussed below. In comparison with doxorubicin, vincristine, vinblastine, paclitaxel, etoposide and 9-amino-campotcin have protein binding regimes above 50%. Normally, protein binding affinity above 25% is preferred, binding above 50% with protein binding above 75% is more preferred, it being more preferred when lung retention is the target. In a preferred formulation and method for treating neoplasms of the pulmonary system by inhalation, the diffusion characteristics of the particular drug formulation through the lung tissues are chosen to obtain an effective concentration and an effective residence time in the tissue to be treated. . Doses can be increased or reduced or can be given more or less frequently to achieve selected blood levels. Additionally, the control of administration time and the amount of the formulation are preferably controlled to optimize the therapeutic effects of the formulation administered in the tissue to be treated and / or titrated at a specific blood level. Diffusion through the lung tissues can be further modified by various excipients that can be added to the formulation to decrease or accelerate the absorption of drugs in the lung tissues. For example, the drug can be combined with surfactants such as phospholipids, dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol. The drugs can also be used together with bronchodilators that can relax the bronchial passages and allow easier entry of the antineoplastic drug into the lung. Albuterol is an example of the latter, with many others known in the art. In addition, the drug can be complexed with biocompatible polymers, micellar structure or cyclodextrins. The particle size of the spray drug used in the present examples was measured from about 2.0 to 2.5 μm with a geometric normal deviation (DNG) of about 1.9-2.0. Typically, the particles should have a particle size of approximately 1.0-5.0 μm with a DNG less than about 2.0 for the deposit within the central and peripheral compartments of the lung. As noted herein, the particle sizes are selected depending on the desired deposition site 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 polyethylene glycol. Powders useful in the invention include drug formulations. pure or drug formulations combined with excipients or vehicles such as mannitol, lactose or other sugars. The powders used herein are effectively suspended in vehicle gas for administration. Alternatively, the powder can be dispersed in a chamber containing a gas or gas mixtures, which is inhaled by the patient.

In addition, the invention includes controlling the deposition patterns and the total dose through careful control of the flow and volume inspired by the patient. This can be achieved using previously controlled pulmonary devices and similar devices. The inventors have shown by gamma scintigraphy measurements that the aerosol deposition of drugs is maximized and evenly distributed in the peripheral lung when the patient inhales using slow flow regimes and inhales maximum lung volumes followed by a short time of hold your breath. The deposition of the central lung is favored when the inspiratory flow regimes are faster and the slower inspiratory volumes are used. In addition, total deposits and doses deposited regionally change significantly as the patient's inspiratory patterns change. Therefore, the method of treatment and the use of delivery devices described herein may be modified for different target regions of the respiratory tract and adjusted for very different doses of the drug delivery. The integration of the molecular weight of the drug, the binding affinity of the protein, formulation, aerosol generation condition, particle size distribution, aerosol delivery interface to the patient via the device and control of the patient's inspiratory patterns, they are what allow the directed and controlled supply of highly toxic anti-carcinogenic drugs to the respiratory tract with the option of minimizing or providing controlled systemic availability of the drug. Example 4 The tests for the administration of doxorubicin by inhalation referred to in Example 3 were repeated substantially at different doses using a different drug delivery system 500 described below. In the present examples 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 / m2 for three days or a total dose of 180 mg / m2. This resulted in a lung deposition of approximately 90 mg / m2. The high dose group was given a dose of 180 mg / m2 daily for three days or a total dose of 540 mg / m2. This resulted in a lung deposition of approximately 90 mg / m2.

Half of the animals were necropsied after three days of exposure and the remaining dogs were necropsied after a recovery period of three days. The purpose of the tests was to identify the maximum tolerated dose of the inhaled drug. For comparison with the results of Examples 2 and 3, the data from mg / kg to mg / m2 (m2 of the body area) can be converted by multiplying by 20 (conversion factor for the dog). Therefore, the exposure of the dogs in Examples 2 and 3 that were equivalent to a clinical dose (for dogs) was approximately 20 mg / m2. When these doses are compared to those of Example 4 (180 mg / m2 and 540 mg / m2), it is evident that a significantly higher dose in the non-encapsulated drug can be delivered to the lung compared to the known technique. Although the dogs that received the lower dose scales showed little toxic effects, while the dogs received the total doses had higher pulmonary toxicity, these doses were 9 to 27 times higher than those generally given clinically to the dogs. . While the present examples used doses of active drug of doxorubicin of about 20 mg / m2, 1 80 mg / m2 and 270 mg / m2, the effective amounts of effective anti-cancer drugs can range from very small amounts to those where Normal toxicity becomes a problem. As used herein, the effective amounts and pharmaceutically effective amounts of the antineoplastic drug deposited or applied to the areas in need of treatment and dosage that reduce a neoplasm or mass your morale, stop your growth or delete it all together. Referring now to Figure 5, the liquid formulation was administered to the dogs by aerosol with a nebulized exposure system r 500 comprising a nebulizer 501 Pari LC J et P l u s ™. The nebulizer was filled with the sol ution of the drug with which the dogs were to be treated. The output of the nebulizer 501 was pulsed in a series of jets with time (one pulse every ten seconds). The nebulizer 501 was directly attached to a 503 volume plenum of 460 cc and the full 403 was connected to an exposure mask only for canine mouth 415 via a short piece of anesthesia tubing 505 and the Y-shaped fittings 507. The mask 415 was tapered to conform approximately to the shape of the dog's muzzle. There was no flow of air driven through the exposure system 500. The test atmosphere was expelled through the exposure system 500 by the inhalation of the dog 501. A one-way breathing valve 513 over the top of the nebulizer 501 allowed the dog 51 1 to extract the air at room temperature and draw air through the system 500. The air was introduced and the drug was transported through the aerosol through of plenum 503, pipe 505, accessory in the shape of Y 507 and mask 415 to dog 51 1. A track valve 515 connected to the Y-shaped accessory 507 allowed the dog 51 1 to exhale and draw exhaled air out of the system. The air supply 520 provided an air flow to the controller 530 via line 521. The nebulizer air flow was controlled by the controller 530 and supplied to the nebulizer via line 531. Referring now to Figure 6, mask 415 is shown in detail. Means for covering the mouth and nose are made of flexible material and are preferably held by Velero ™ strips or bands. The wrapping means 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 attaching the nose outlet tube 61 1. The nose outlet tube 61 1 has a one way valve 612 that allows the dog to exhale but not inhale through its nose. The mouth tube 621 is inserted and connected to the opening 609 and is inside the wrapping means 601. An optional Y-shaped connector 623 can be connected to the mouth tube 621 to provide and receive the inhaled and exhaled gases. Air is generally inhaled through the tip 625 of the Y-shaped connector. Air passes through the mouth tube 621 and out of the inner opening 631 into the dog's respiratory system. The internal opening 631 is cut at an angle with its lower portion 633 extending further into the dog's mouth than the upper portion 635. The lower portion 633 functions to press the dog's tongue and allow the dog more efficient entry of the dog's flow. air and spray. When the dog is wearing the 415 mask, he can only breathe through his mouth using the mouth tube 621. The wrapping means 601 effectively seals the mouth of the dog and the nose of the external air. It has been found that the use of an external nose tube 61 1 makes it very easy for dogs to wear the mask. The exhaled air through the mouth exits through the mouth tube 621 and passes in a Y-shaped connector optionally connected to another tube not shown. The air leaves the connector in the form of Y 623 via the outlet tube 627. If desired, the Y-shaped connector 623 or another external tube (eg straight pipe) can be formed in one piece and simply pass in the wrapping means 601 or can separate the pieces that fit together. In any case, an adapter 637 can be used to hold it in the mouth tube 621 or another pipe to which it is connected. A general device for administering aerosols to a patient includes an inhalation mask to administer aerosols to the inclusion means to cover the mouth and nose of the patienthaving an open end and a closed end, the open end adapted to be placed over the mouth and nose of the patient; the upper and lower holes at the closed end, adapted for the insertion of an external tube of the nose and an inhalation tube of the mouth; the nose outlet tube connected to the upper hole adapted to accept exhaled breath from the patient's nose; a one-way valve in the nose tube adapted to allow exhalation but not inhalation; the inhalation tube of the mouth having an external and an internal end, inserted partially through the lower hole, the inner end continuing to the end in the back of the patient's mouth, the end of the inhalation tube is cut at an angle in the manner that the lower portion extends more in the patient's mouth than in the upper portion and adapts to adjust the curvature of the posterior part of the mouth; and a Y-shaped adapter connected to the outer end of the mouth inhalation tube. Pulmonary administration by inhalation can be achieved by the production of liquid or powdered aerosols, for example, by the devices described herein or by using any of the various devices known in the art.

(See, e.g., Newman, SP, 1984, in Aerosols and the Lung, Clarke and Davia (Eds.), Butterworths, London, England, pp. 197-224; PCT Publication No. WO 92/16192 filed on October 1, 1992; PCT Publication No. WO 91/08760 filed on January 27, 1991; Patent Application of NTIS 7-504-047 filed on April 3, 190 by Roosdorp and Crystal) including but not limited to limited to nebulizers, metered dose inhalers and powder inhalers. Several supply devices are commercially available and can be used, e.g. , Ultravent Nebulizer (Mallinckrodt, Inc., St. Louis, MO); Acrn I I Nebulizer (Marquest Medical Products, Englewood, CO); Metered dose inhalers of Ventolin (Glaxo Inc., Research Triangle Park, North Carolina); Spinhaler powder inhaler (Fisons Corp, Bedfor, MA) or Tubohaler (Astra). Said devices normally cover the use of suitable formulations for dispensing from said device, in which a propellant material may be present. Ultrasonic nebulizers can also be used. Nebulizer devices such as those in the Patents of E. U.A. Nos. 5, 51 1, 726 and 5, 15, 971 of Greenspan et al. Are useful in the invention. These devices use electrohydrodynamic forces to produce a finely divided aerosol that has droplets dimensioned uniformly by electrical atomization. While Greenspan devices use piezoelectric materials to generate electrical power and a source of power is acceptable to produce electrohydrodynamic forces for ja nebulization. A nebulizer can be used to produce aerosol particles, or any of several physiologically inert gases can be used as an aerosol agent. Other components may also be included such as physiologically acceptable surface active agents (e.g., glycerides), excipients (e.g., lactose), vehicles (e.g., water, alcohol) and dioluents. As will be understood by those skilled in the art to deliver pharmaceuticals via the pulmonary route, a primary criterion for the selection of a particular device for the purpose of producing an aerosol is the size of the resulting aerosol particles. Smaller particles are needed if the drug particles are primarily or only intended to be delivered to the peripheral lung, ie the alveoli (eg, 0.1-3 μm), while the larger drug particles are needed. (e.g., 3-10 μm) and are supplied solely or mainly to the central pulmonary system such as the upper bronchi. The impact of particle size on the deposit site 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 and others (Aerosol Science; Vol. 4; 1973, pp. 35-45) (Figures 6 7 and 8 of the article) and The Task Group on Lung Dynamics (Figures 1 1 and 14 of the article). As a result, major cancers in the naso-pharyngeal or oral-pharyngeal region and superior tracheo-bronchial regions, often referred to as head and neck cancers, can be treated with the present invention. The major metastatic sites (lung and upper respiratory tract) are also easily treated with this invention simultaneously, unlike current methods of treatment. Referring now to Figure 7, a nebulizer apparatus 700 is described which is preferably portable for administration of the 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 the drugs having properties adapted for the optimal treatment of neoplasms as discussed herein. Figure 7 is a schematic of a nebulizer combination according to the present invention. The nebulizer 701 can be any nebulizer as described hereinabove, which is capable of producing the particle sizes required for the treatment. In combination with the nebulizer 701, a highly toxic drug formulation 703 is provided for the treatment of neoplasms, as described herein. An air supply 705 is provided either as a tank of compressed gas or as a motorized pump or fan to move air from the room. An optional mouth piece 707 can be used when it is necessary to provide sealed contact between the nebulizer and the patient. Optionally, mouthpiece 707 can be molded as part of nebulizer 701. The energy for using the nebulizer apparatus 700 can come from the compressed gas of manual manipulation by the user or administered by batteries or electric power, not shown, but well known to those skilled in the art. To control the environmental contamination that results from the use of a nebulizer, the patient can be placed in a well-ventilated area with the filtered escape area to remove antineoplastic drug that escapes from the device. Examples 5 to 11 Examples 5F to 11F show the feasibility of inhalation and carry out the concept tests and Examples 5R and 10R show the dose increase scale examinations: with vesicant antineoplastic drugs including doxorubicin, paclitaxel, vincristine, vinorelbine; non-vesicant drugs including etoposide and 9-ammonicampotcin (9-AC) and carboplatin. The drugs are delivered to the pulmonary system via aerosol at a particle size of about 2 to about 3μm. The drugs were delivered in water or other devices appropriate for the drug as is known in the art and as simplified herein. Table 7 illustrates the dose schedule for studies of finding scales. A minimum of 7-14 days separated each dose increase. There were no tests to find scales, only feasibility tests, for mitomycin-C and 9-AC. Feasibility tests were not carried out, only tests to find the dose scale for vinorelbine. It is important to note that the doses listed in Table 7 are the doses deposited pulmonarily, not the total doses administered. Feasibility results and dose increase studies are summarized in Tables 7 to 11.

TA BLA 7 Régime of Increase of Dose for Studies to Find the Scale Average Dose Deposited Pulmonary 00 N otes: A minimum of 7-14 days separated each scale increase Animals that were killed after the last dose.

The animals used in Examples 5 to 11 were adult beagie dogs. For the feasibility of the studies, the dogs were initially given a single intravenous (IV) dose of antineoplastic drug. This dose was given to allow a comparison of when the drug had been absorbed into the blood after inhalation compared to the IV supply. The IV dose given was usually the usual human clinical dose that had been decreased for dogs based on differences in body mass, or the maximum tolerated dose in the dog, whichever was greater. An average human who weighs 70kg is considered to have a weight to body surface ratio of 37 kg / m2 and a lung surface area of 70-100 m2 of lung surface area. The average dog used in the tests was considered to have a weight of 10kg corresponding to a weight ratio to body surface of 20 kg / m2 and a lung surface area of 40-50 m2 of lung surface area (CRC Handbook of Toxicology 1995, CRC Press Inc.). The only IV dose was used to quantify plasma kinetics. With the majority of the cytotoxic agents treated, the single IV dose resulted in a predictable moderate release in white blood cell content, without other measurable toxicities. After the IV and before the inhalation feasibility tests, the dogs were given a period of inactivity of at least seven days (until the dogs returned to normal conditions) before they were treated with inhaled antineoplastic drugs. . In the inhalation feasibility tests, the dogs were generally exposed to an inhaled aerosolized antineoplastic drug dose once a day and for three consecutive days (except as noted in Tables 8 to 11) and the necropsy one day after the last dose with the plasma kinetics characterized after the first and third exposures. With the exception of cisplatin and the high dose of doxorubicin, which caused toxicity to the respiratory tract, the drugs did not exhibit any significant pulmonary toxicity in these inhalation feasibility studies of repeated exposure. In the feasibility tests, the dogs used the same mask and devices used for the previous examples. In the tests to find the dose scale, in order to control the dose deposited, the dogs were conditioned with an endotracheal tube and the drug was administered as an aerosol directly from the endotracheal tube. This last procedure made it easier to control the dose deposited pulmonarily because the aerosol was released directly into the passages of pulmonary air ensuring the deep deposit of the drug in the lung. Also the use of the endotracheal tube made it possible to perform the tests in a shorter time because the dogs needed a training period of four to six weeks to acclimate and use the masks properly. The calculated deposited doses obtained herein were experimentally verified by pulmonary scintigraphy tests in dogs.

Examples 5F and 5R Referring now to Table 8, this table shows the details of the paclitaxel feasibility tests. Initially the dogs were administered 120 mg / m2 of paclitaxel per IV. After the inactivity period, the dogs were administered a total deposited dose of 120 mg / m2 of paclitaxel, by inhalation, three times for a total deposited dose of 360 mg / m2. This administered dose resulted in a lung deposited dose of approximately 20 mg each time or a total lung dose of approximately 81 mg. This represents a deposited lung dose of approximately 2.1 mg / m2 of the surface area of the lung. The doses were calculated as follows: the doses of 120 mg / m2 were divided between 20 kg / m2 to give a dose of 6 mg / kg that was multiplied by 10 kg for the average dog, in order to give approximately 60 mg of the drug. Because the masks were used for administration of the drug, half or about 30 mg of the drug was considered deposited in the deep lung. Since the drug was administered three times, the exposure of the total drug was approximately 90 mg. The 90 mg of the drug was divided by 40 to give a total lung dose of approximately 2.25 mg / m 2 of the surface area of the lung. The clinical condition of the dogs was normal. The clinical pathology profiles were normal with only moderately reduced white blood cell counts. Hystopathology showed bone marrow and lymphoid depletion, G1 hairy atrophy and congestion and laryngeal inflammation. These changes indicated that some significant fraction of the drug deposited was absorbed systemically. No toxicity of the respiratory tract was found. The bioavailability of paclitaxel was found to be low to moderate based on plasma kinetic evaluations. The low to moderate bioavailability indicates that the majority of paclitaxel remained in the lungs and did not enter the systemic circulation rapidly in large quantities. Therefore, due to the lack of significant direct respiratory tract toxicity, the toxicity that limits the probable dose is considered to be myelosuppression and / or Gl toxicity. The factors intrinsic to the lung are expected to limit the doses provided by the pulmonary route. Referring again to Tables 7 and 8, in the tests to find the scale, 60 to 120 mg / m2 of paclitaxel were administered at intervals per week for five weeks. The amount of lung deposited dose ranged from about 30 to about 60 mg. This scale corresponds to approximately 0.75 to about 1.50 mg / m2 of the lung surface area. The clinical conditions of these dogs were normal, with changes in clinical pathology limited to a reduction in the moderate white blood cell count. Histopathology showed thoracic and mesenteric lymphoid exhaustion along with inflammation G l and ulceration. The histopathology reflects that inflammation was found in the IV administration of paclitaxel, in particular Gl and ulceration associated with paclitaxel administered systemically. The toxicity of the respiratory tract indicated minimal interstitial pulmonary inflammation. The systemic bioavailability was proportional to the dose. The probable dose that limits the toxicity is myelosuppression and Gl toxicity and non-pulmonary toxicity.

TABLE 8 -Paclitaxel Summary of Results of Feasibility Studies of Dogs and to Find Dose Scales * - Divide the dose deposited pulmonarily in mg by 40 to obtain the dose deposited pulmonarily in mg / m2 of the surface area of the lung. CGB - white blood cell count Example 6F and 6R Referring now to Table 9, initially 20 mg of doxorubicin was administered by IV. After a period of inactivity, three groups of inhalation feasibility tests were done. In the first, a single dose of 20 mg / m2 of doxorubicin was administered which gave approximately 20 mg of body dose, a lung deposited dose of approximately 5 mg to around 0.125 mg / m2 of the surface area of the lung. No changes were observed in the animal of this dose. A second group of moderate inhalation doses of approximately 40 mg / m2 of doxorubicin (approximately 10 mg deposited within the lung) was administered three times from one to three consecutive days. The total cumulative dose administered was 120 mg / m2 corresponding to about a body dose of 60 mg and a total lung deposition dose of approximately 30 mg (or approximately 0.75 mg / m2 of the surface area of the lung). A third group of high doses of inhalation 120 mg / m2 of doxorubicin was administered three times per day for a period of three days for a total dose of 360 mg / m2 corresponding to 180 mg of body dose, a dose deposited pulmonary total of approximately 90 mg or around 2.25 mg / m2 of lung surface area. Half of the dogs in the low dose group were necropsied the day after the final exposure and the other half were necropsied four days later. All dogs with high doses underwent necropsy on the day following the final exposure. Exposure to these extremely high doses resulted in the death of a group of dogs from the high dose group after three days of exposure, killing the three remaining dogs in moderately weakened to dying conditions. This intensive dose treatment caused pulmonary edema, a sequelae of microscopically recognizable degeneration, necrosis and inflammation of epithelial surfaces that cover the bronchi and larynx and the mucosal surfaces of the nose and lips. These lesions threatened life and were more severe in the high dose group, but were considered survivors at lower doses, based on the clinical condition of the animals. Despite these higher doses, there were no changes in clinical pathology that indicated myelosuppression induced by doxorubicin. There was microscopic evidence of lymphoid depletion at the regional lymph nodes of the respiratory and gastrointestinal tracts suggesting regional drainage of free doxorubicin to lymph node drainage of the thoracic and G l systems. The CWB values actually increased in the high dose group, a change associated with the inflammatory response observed in the respiratory tract. There were no other changes in clinical pathology that serum alkaline phosphatase increased in the high-dose group, a non-specific change, due to the likelihood of tissue damage of the respiratory tract.

Generally, the changes observed in moderate to high doses were edema, increased white blood cell count and increased respiratory regimen. Histopathology revealed thoracic lymphoid depletion and Gl for the moderate to upper dose, respectively. Toxicity of the respiratory tract, including epithelial degeneration of respiratory airways and moderate to severe inflammation, was observed at increased doses. The bioavailability was low to moderate indicating a process of limiting the rate of absorption of movement of the drug in the systemic circulation. The likely dose limiting toxicity of doxorubicin is expected to be respiratory tract toxicity rather than systemic toxicity. further, a dose increase study was carried out in a weekly exposure program. The initial doses of 12 mg deposited were delivered via the endotracheal tube to the lungs, with doses in the fifth week of 18 mg deposited inside the lungs. This provided a total body dose of 24 to 36 mg / m2. The results of this repeated route study were similar in character (but not in severity) to studies of higher doses. The animals survived this treatment regimen with minimal clinical evidence of toxicity and there was no evidence of systemic changes. Histologically, there was no evidence of epithelial degeneration of the respiratory tract and inflammation.

TABLE 9 -Doxorubicin Summary of Results of Feasibility Studies and to Find Dose Scales for Dogs t - Increase, i Decrease RRI - Increased respiratory rate, CGB white blood cells. * - Divide the lung dose deposited in mg by 40 to obtain the lung deposited dose in mg / m2 and surface area of the lung The plasma levels of doxorubicin were the doses that depended and exhibited clear evidence of drug accumulation, including daily increases in Cmax (maximum concentration in blood) and profiles similar to the resting state, suggesting that there was limited absorption in the lung regimen in blood with significant accumulation of doxorubicin in the lungs after each given exposure at a frequency of daily intervals. This accumulation was probably considered responsible for the tissue damage observed. Referring again to Table 7 and 9, it was administered at an inhalation dose scale of 20-40 mg / m2 in five weekly doses which resulted in a body exposure of about 10 mg to about 20 mg, a lung deposited dose scale of about 10 to about 20 mg or a scale of about 0.25 mg / m2 to about 0.5 mg / m2 of surface area of the lung. The clinical condition included included increased respiratory regimen and mild temporal pulmonary edema. A decrease in the white blood cell count was observed for the higher doses. Histopathology revealed mild to moderate thoracic and mesenteric lymphoid exhaustion. The respiratory tract toxicity observed was a mild to moderate degeneration of the airway epithelium. We observed a mild to moderate interstitial inflammation marked by some limited fibrosis. Bioavailability was observed from low to moderate with absorption being limited. The toxicity of dose limitation probably seems again to be respiratory tract toxicity. Example 7F and 7R Referring now to Table 10, initially 1.4 mg of vincristine was administered by IV. After the inactivity period, an inhalation feasibility test was performed. The vincristine was formulated in a vehicle of 50% water / 50% ethanol. A single dose of 2.8 mg / m2 of vincristine was administered which gave approximately 1.8 mg of body dose, a lung deposited dose of approximately 0.9 mg or approximately 2.25 mg / m2 of lung surface area. No changes were observed in the animal from this dose.

TABLE 10 - Vincristine and Vinorelbine Results of Summary of Feasibility Studies and Finding of Dose Scale in Dogs 00 f - Increase, i Decrease RRI - Increased respiratory rate, CGB white blood cells. * - Divide the lung dose deposited in mg by 40 to obtain the lung deposited dose in mg / m2 and surface area of the lung Referring now to Tables 7 and 10, the inhaled vincristine scale finding tests were performed on the scale of 0.5 to 1.5 mg of vincristine deposited pulmonarily administered in six weekly doses. Therefore, the amount of doses deposited pulmonarily varied from 12.5 to 37.5 μm / m2 of the surface area of the lung. This corresponded to a total body dose of 50-150 μg / kg or 1.0-3.0 mg / m2 of the surface area of the body. This dose scale is almost generally above the normal dose scales of vincristine given IV. But in the examples given herein, the entire dose was administered to the lungs. Vincristine is a potent drug and causes myelosuppression and neurotoxicity at doses above 1.0 mg / m2 given systemically. The results of the pilot inhalation studies showed that the drug was tolerated well at the doses delivered by the pulmonary administration with little or no evidence of respiratory tract toxicity with moderate lymphoid depletion / myelosuppression only occurring at the highest doses given ( 2.0-3.0 mg / m2). EXAMPLE 8R Vinorelbine, which is also an alkaloid vinca, was evaluated in a pilot test of repeated exposure. Compared with vincristine, vinorelbine was approximately 5-10 times less potent to produce toxicity, but produced similar types of changes. Vinorelbine supplied by pulmonary administration was well tolerated directly to the lungs of the dogs through the endotracheal tube, on a weekly basis (for 5 weeks) at increased doses. A dose of 6 mg deposited in the lung was initially selected and elevated to 15 mg deposited within the lung. This represents a lung surface exposure of ~ 0.1 5-0.375 mg / m2 of lung surface area and total body dose of 12-30 mg / m2. This treatment regimen produced quite minimal effects within the respiratory tract, mainly characterized by slight inflammation. At higher dose levels, inhaled vinorelbine produced sufficient blood levels to cause myelosuppression and depletion of mild to moderate lymphoid, which were reversible and of such severity that they did not threaten life. Examples 9F and 9R A further test of inhalation studies pilot of concept implied etoposide. Etoposide is a cytotoxic drug, representative of a class of drugs known as topoisomerase I I inhibitors. Given orally or IV, the etoposide causes normal cytotoxic systemic toxicity, including myelosuppression, severe Gl toxicity, and alopecia. The etoposide is a highly insoluble drug, therefore difficult to formulate. The vehicle used clinically also causes adverse effects, predominantly anaphylactic reactions. In this invention, the etoposide was reformulated in a novel vehicle, dimethylacetamide (DMA) that does not cause anaphylactic reactions. While DMA can not be used for IV administration due to systemic toxicity, it was shown to be a safe delivery vehicle for the pulmonary delivery route. The etoposide was delivered in a vehicle with 100% DMA. This formulation allowed the formation of the appropriate particle sizes. In these tests, increased doses of etoposide were given to dogs on a weekly schedule. The initial dose used was 25 mg of etoposide deposited in the lung region with a sixth dose of 80 mg, and final, delivered deposited within the lung region. This was matched to a dose scale of 50-160 mg / m2 of body surface area. This treatment regimen did not cause systemic toxicity and only minimal inflammation of the lung and there was no damage to the respiratory tract. In addition, there was good evidence of llnfoid depletion of the thoracic lymph nodes, in the absence of systemic changes, indicating that the drug was drained directly through the regional lymphatic system. This could provide additional regional therapeutic effectiveness in dealing with metastatic cells. A further pharmacokinetic test of the inhaled etoposide showed that the drug had moderately good bioavailability. A single inhaled total deposited dose of 260 mg / m2 (approximately 65 mg of the drug deposited in the lung region) produced similar etoposide blood levels at an IV dose of 50 mg / m2 (see Figures 1 -3). In other words, to achieve blood concentrations similar to approximately 5 times more of the drug was inhaled, a dose that did not cause toxicity in the respiratory or systemic tract. Example 10F The additional test of the concept inhalation studies involved the cytotoxic drug 9-aminocampotcin (9-AC) which is within the class of drugs known as campotins. The similar etoposide, 9-AC is insoluble and difficult to formulate. Supporting the concept and claims of this invention, the inventors generated 9-AC aerosols formulated as a microsuspension in an aqueous vehicle (100% water) . These aerosols were delivered to dogs at daily doses of 40 mg / m2 body surface area (10 mg of the drug deposited within the lung region) for 3 consecutive days. Inhalation treatment resulted in lower plasma levels of the drug at an IV dose of 10 mg / m2. The daily inhalation dose was 4 times higher than the IV dose and the inhalation dose on the 3 cumulative total day was 12 times higher than the only given IV dose (which causes moderate systemic toxicity). Despite the significantly higher doses given by inhalation, there were no measurable toxic effects (neither local effects within the respiratory tract nor systemic changes). The results of these tests supported the concept of improved overall safety and dose intensification within the respiratory tract and also demonstrated the concept with aerosol microsuspensions of chemotherapeutic drugs. Example 1 1 F In addition, this feasibility study was extended to examine other chemotherapeutics containing platinum, carboplatin. The usual clinical formulation using water was used. Carboplatin is generally considered less toxic than cisplatin at comparable doses and this seemed to agree with the results observed when the two agents were delivered by inhalation. Inhaled doses of up to 30 mg of carboplatin deposited via the endotracheal tube in the lungs of the dogs (60 mg / m2 of total body dose) did not cause direct evidence of the respiratory tract or systemic toxicity.

TABLE 11 -Etposido and 9-Aminocampothecin (9-AC) Summary Results of Feasibility Studies and Find Dose Scales in Dogs OD - Divide the lung dose deposited in mg by 40 to obtain the lung deposited dose in mg / m and surface area of the lung Examples 12 to 20 These examples illustrate clinical treatment results of dogs that have late stage lung cancer had failed other treatments. For the treatment, the dogs were anesthetized and the inhalation treatment was through an endotracheal tube. This preliminary study was conducted to determine if inhalation chemotherapy treatment could be used successfully in animals with lung tumors. Initially, nine dogs with lung disease were studied. Three different groups, doxorubicin, vincristine, cyclophosphamide, cisplatin, and paclitaxel were used at the doses and schedules summarized in Table 12. A mixed-breed 16-year-old dog that had no evidence of lung tumor after excision of the lungs. a primary lung tumor, but had evidence of metastasis in the hilar lymph nodes, a sign that metastasis may soon appear in the lung. However, the results showed that metastasis in the lung did not develop for four months, during which time the dog received four doxorubicin treatments. In another six dogs, there was metastasis in the lung and in each one of them, the inhaled chemotherapy stopped the growth in the metastasis, that is, there was stable disease (or EE). In two dogs inhalation chemotherapy was not effective and there was progressive disease (or PD). Because these dogs were not given therapy by intravenous route, the tumors outside the lung progressed although the tumors in the lung stabilized. Therefore, the results showed that inhaled chemotherapy was effective in the local treatment of lung cancer in dogs.

TABLE 12 Summary of Preliminary Clinical Results in Dogs < o o - Calculate white dose. Abbreviations: EP = progressive disease, EE = stable stability; Dox Doxorubicin; CTX = cyclophosphamity; CS = every week Example 21 to 33 Additionally, the tests were carried out on dogs using a defined protocol. In these tests, dogs with gross metastatic disease, micrometastatic hemangiosarcoma or micrometastatic primary lung cancer were randomized to receive doxorubicin, paclitaxel or both by inhalation via an endotracheal tube in a cross-over design. The aerosol particle size was 2 - 3 μm as in the previous tests. The apparatus used was basically that shown in Figure 5 and as described above, the formulations for the administration of the dogs were as follows: 16 mg / ml doxorubicin in 70% ethanol / 30% water; 75 mg of paclitaxel in approximately 30% PEG / 70% ethanol. Preferably paclitaxel was administered with 0.2% citric acid to prevent degradation of the drug unless it was used immediately after the preparation. The treatments were administered once every two weeks and if a diagnosis of progressive disease was made in two consecutive intervals, the dog was crossed with the alternative drug. At each treatment session, blood samples were taken for hematology from biochemical analysis and the urine was recovered for analysis. The state of the tumors was monitored radiographically.

The results are summarized in Table 12. The doses deposited pulmonarically listed in the table are based on scintigraphy studies that relate the inhaled doses to the doses deposited. Among the 10 dogs that had gross metastatic disease (Examples 21-28), which was considered as a terminal condition with a very short life expectancy, 4 dogs (in Examples 21, 22, 24 and 27) showed stable disease in the lung indicating that the drug had a positive effect. In the remaining 6 dogs (see examples 23, 25, 26 and 28), lung disease progressed. In two of the dogs with metastatic osteosarcoma (Examples 24 and 25) and in the dog with metastatic melanoma (Example 28), there were partial responses, that is, there were tumors that decreased in size by more than 50%. Four dogs had splenic hemangiosarcoma (Examples 29 and 30), a disease that invariably metastasizes to the tumor and is fatal within two to four months. These dogs were given doxorubicin by inhalation in addition to intravenous chemotherapy to control the systemic disease. The results in Table 13 show that each of the four dogs was alive (at least two months at this time) and there was no evidence of lung disease. The last groups of dogs (Examples 31-33) are those that had primary lung tumors which were surgically removed. 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 without evidence of disease 81 days after suggesting that the treatment is having a positive effect. One dog (Example 32) received two doses of doxorubicin and died of metastases outside the lung. The other two dogs (Example 33) had no evidence of disease but did not spend enough time to determine how effective the treatment would be. The result of these tests, therefore, confirms those preliminary tests that inhalation chemotherapy is effective for the treatment of lung cancer. Table 13 Efficacy of Inhalation Chemotherapy in Dogs with Lung Cancer DOX = doxorubicin; (x) = number of treatments received; EE = stable disease; EP = progressive disease, ESS = no evidence of disease; RP = partial response (50% decrease in tumor size).

The safe and effective dose scale of inhaled antineoplastic drugs in humans and animals (e.g., buts and similar small animals) are shown in Table 14 below. Doses for larger animals can be calculated using multiples of the doses based on small animals based on the known ratio of (body weight in kg / m body surface area). The exact doses will vary depending on such factors as the type and location of the tumor, the age and size of the patient, the physical condition of the patient and the concomitant therapies that the patient may require. The doses shown are for doses of a course of therapy. A course of therapy can be given monthly, weekly, biweekly, in three weeks or daily, depending on the drug, patient, type of disease, stage of the disease and so on. The safe and effective amounts of the vehicle given for each product are given by the respective manufacturer and summarized in the Physicians Desk Reference. Table 14 * - m body surface area Based on the results of the inhalation tests herein with doxorubicin, inhalation treatments with anthracyclines in addition to doxorubicin are also expected to be tolerated and effective when administered by the pulmonary route.

Based on the present inhalation tests with vincristine and vinorelbine, it is expected that other vinca alkaloids are well tolerated and effective when administered by the pulmonary route. Based on similar tests of the present for doxorubicin, vincristine, vinorelbine and paclitaxel visicants, all of which are capable of serious vesicant damage, other vesicant drugs (e.g., mechlo-thymeline, dactinomycin, mithramycin, bisantrene, amsacrine, epurubicin, daunorubicin, idaurubicin, vinblastine, vindesine and so on) are expected to be well tolerated and effective when administered by the pulmonary route. Of course, the exception could be vesicant drugs that are known to exhibit significant pulmonary toxicity when administered by IV (eg, mitomycin-C). In this regard, a safe and effective amount of a particular drug and agent of the amount that is based on its potency and toxicity, provides the appropriate efficacy / risk balance when administered by pulmonary means in the treatment of neoplasms. Similarly, a safe and effective amount of a vehicle or carrier is the amount based on its characteristics of solubility, stability and aerosol formation characteristics, which provides the required amount of a drug to the appropriate site in the pulmonary system for the treatment of the neoplasm. . For non-vesicant antineoplastic drugs, based on the inhalation tests herein for the vesicant and non-vesicant drugs, it is expected that all non-vesicant drugs do not exhibit direct pulmonary toxicity when administered intravenously and are expected to be well tolerated and exhibit efficacy. For example, bleomycin and mitomycin-C, exhibit sufficient lung toxicity that will be excluded except when a chemopreventive agent is used. In this regard, carmustine, dacarbazine, melphalan, methotrexate, mercaptopurine, mitoxantrone, esorubicin, teniposide, aclacinomycin, plicamycin, streptomycin, menogaril are normally expected to be well tolerated and exhibit efficacy. Similarly, currently unknown classification drugs such as geldanamycin, briostatin, suramin, carboxyamido-triazoles such as those in the patent of E. U.A. 5, 565,478, oncanase and SU 101 and its active metabolite SU20, likewise, are expected to be well tolerated and exhibit efficacy subject to limitation on pulmonary toxicity. These drugs could be administered by the same methods described for the antineoplastic drugs tested. They could be formulated with a safe and effective amount of a vehicle and administered in safe and effective amounts and a dosing schedule to treat neoplastic disease. The pulmonary toxicity of compounds that have been administered by inhalation is an important consideration. As mentioned before, one of the main considerations is whether the drug exhibits significant pulmonary toxicity when injected by IV. While almost all antineoplastic drugs are toxic to the body and therefore exhibit arguably lung toxicity if given in a sufficiently large dose, the pulmonary toxicity test as used herein requires significant pulmonary toxicity at the highest dose recommended by the manufacturers to be administered even patient. The determination of whether a drug exhibits sufficient pulmonary toxicity by IV so as to exclude it from the group of drugs useful for pulmonary administration, can be done from the recommendations of the drug manufacturer as published in the Physicians Desk Reference (see "Physicians Desk Reference "1997, (Medical Economics Co.), or the latest editions of it), in other published drug handbooks for those who provide health care, presentations publicly available with the FDA or the literature distributed directly by manufacturers to physicians , hospitals and the like, for example in "Physícians Desk Manual "1997: • Doxorubicin (Astra) pp. 531-533-Vesicant, there is no indication of pulmonary toxicity, while if it is cardiac toxicity, haematological toxicity, particularly leukoponia and myelosuppression, extravasation damage is also observed • Idarubicin (Pharmacia & amp;; Upjohn) pp. 2096-2099 - vesicant, primary toxicity appears to be myelosuppression, no mention is made of pulmonary toxicity making the drug useful in the present invention: • Etoposide (Astra) pp. 539-541 - No indication of pulmonary toxicity, but haematological toxicity that limits the dose is important • Paclitaxel (Bristol-Meyers Squibb) pp. 723-7237 - vesicant, pulmonary toxicity is not ready for paclitaxel, but bone marrow suppression is important (neutropenia mainly ) • Bleomycin (Benoxane® Bristol-Meyers Squibb) pp. 697-699, the main toxicities occur in about 10% of patients treated with the drug adm Inistrado IV, this makes bleomycin unacceptable for pulmonary administration for the present invention; • Mitomycin C (Mutamycin® Bristol-Meyers Squibb) - vesicant, uncommon lung toxicity has been presented but, if life threatens severely by IV administration, this pulmonary toxicity that threatens severe but not frequent life shows that the drug exhibits substantial lung toxicity; • Methotrexate (Immunex) p. 1322-1327 -PM = 454, primary toxicity appears to be hepatic and hematologic, signs of pulmonary toxicity should be monitored closely for signs of injury; • Dactinomycin (Merck &Co.) - vesicant the primary toxicity seems to be oral, gastrointestinal, hematological and dermological; no mention is made of pulmonary toxicity making the drug acceptable in the present invention; • Mechlorethamine (Merck &Co.) - vesicant, the primary toxicity appears to be renal, hepatic and bone marrow, no mention is made of the pulmonary toxicity that makes the drug acceptable in the present invention; • Irinotecan (Camptosar® Pharmacia &Upjohn) - a camptotcina derivative, the primary toxicity resembling severe diarrhea and neutropenia, no mention of pulmonary toxicity making the drug useful in the present invention; Iianrciiic, UIÍ CI niuu i au m iuyc upcr? piupratron • Vincristine (Oncovin® Lilly) p. 1521-1523 - extremely toxic with vesicant activity found in the tests herein, but without observed pulmonary toxicity; • Vinblastine (Velban® Lilly) p. 1537-1540 - extremely toxic with high vesicant activity found in the tests herein, but without observed pulmonary toxicity. The above list is illustrative only and is not intended to limit the scope of the invention. A further embodiment of the invention includes methods and formulations that contain chemopreventive agents and are administered by inhalation to avoid the toxicity and particularly pulmonary toxicity that may be produced by antineoplastic drugs. The method may allow the use by inhalation of antineoplastic drugs that exhibit pulmonary toxicity that may reduce the likelihood of pulmonary toxicity. A method could include treating a patient having a neoplasm, via administration by inhalation, a pharmaceutically effective amount of a highly toxic antineoplastic drug and a pharmaceutically active amount of a chemoprevent, wherein the chemoprevent reduces or eliminates the toxic effects on the patient. the patient who was the result of the inhalation of the highly toxic antineoplastic drug. Closer, another embodiment includes a combination of chemopreventive and inhaled anti-neoplastic drug that reduces or eliminates toxicity of the respiratory tract or pulmonary tract in the patient. The chemopreventive can be coadministered with the antineoplastic drug by inhalation or both by inhalation and by IV, or the chemoprotectant can be administered alone. It is known, for example, that when dexrazoxane (ICRF-187) is given by intraperitoneal injection to mice, it protects against bleomycin-induced lung damage given by subcutaneous injections. See for example Herman, Eugene et al., "Morphologic and morphometric evaluation of the effect of ICRF-187 on bleomycin-inuced pulmonary toxicity", Toxicology 98, (1995) p. 163-175, the text of which is incorporated by reference as if it were completely rewritten in the present. Mice previously treated with intraperitoneal injections of dexrazoxane before bleomycin was injected subcutaneously showed reduced pulmonary alterations, particularly, fibrosis compared to another group of mice that were not previously treated. The following examples illustrate the use of a chemopreventive by inhalation together with an antineoplastic drug. Example 34 Dexrazoxane (ICRF-187) was dissolved in a pharmaceutically acceptable liquid formulation and administered to a patient such as an aerosol using the apparatuses and methods described herein, at a dose ranging from 10 mg to 100 mg for a period of time. time from one minute to one day before giving a chemotherapeutic drug such as doxorubicin by inhalation. Doxorubicin is given in a dose of 1 mg to 50 mg. Example 35 Dexrazoxane (ICRF-187) is administered as described in Example 34 at the same time or up to two hours before bleomycin is given by intravenous injection. The dose of dexrazoxane varies from about 2 times to about 30 times the dose of bleomycin. The dose of bleomycin by IV varies from approximately 5 to 40 units / m2. Example 36 Dexrazoxane (ICRF-187) is administered as described in Example 34, at the same time or up to two hours after bleomycin is administered by inhalation. The dose of dexrazoxane varies from about 2 times to about 30 times the dose of bleomycin. The dose of bleomycin by inhalation varies from approximately 5 to 40 units / m2 at intervals of 1 week to 4 weeks. Examples 37 and 38 Chemoprotectants such as mesna (ORG-2766) and etiofos (WE2721) can be used in a manner similar to that described in Examples 34 to 36, above. Combination Therapy Another embodiment of the invention contemplates coadministration of the drug by the pulmonary route; and by (1) other local routes and / or (2) sistémicamente by IV. The results of clinical tests in dogs indicate that, although the pulmonary route of administration controls neoplastic cells arising in or metastatic to the pulmonary tract, neoplastic cells in any other part of the body may continue to proliferate. This modality provides effective doses of drug in the lung delivered via the lung and supplied by additional drug via (1) other local sites (eg, tumors in the liver that can also be treated via hepatic artery instillation, ovarian cancer by intraperitoneal administration) and / or additional drugs that can be provided systemically by IV via the general circulatory system. The administration may be at the same time, or the administration may be followed for a time by one or more of the other therapeutic routes. The benefits are that much higher doses can be delivered to affected tissues and effective control of neoplasms can be maintained at multiple critical sites compared to the use of a single mode of administration. Also within the scope of the invention, the mixture of drugs is contemplated to combine the chemotherapy treatments. The benefits are those well known in the treatment of cancer using combination chemotherapy by other routes of administration. For example, the combination of 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.

Also included in the invention are embodiments comprising the method for inhalation therapy described herein and the application of radiotherapy, gene therapy and / or immunotherapy. Other modalities include the method mentioned immediately above combined with chemotherapy applied by IV and / or local therapy. Also within the invention, paciitaxel formulations are included. In these formulations it is useful between 100% to 40% ethanol. However, for better control of particle size and stable aerosol generation, the addition of polyethylene glycol (PEG) is preferred. Although 1 to 60% PEG can be used, more than 8-40% PEG is preferred and 10-30% PEG was found to be optimal. 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 with respect to clinical use in inhalation, it has been found that citric acid in water causes tingling and bronchoconstrictor effects. PEG can alleviate this effect. The formulation contains a safe and effective amount of paclitaxel useful for the treatment of neoplasms. While the present invention forms described are currently preferred embodiments, many others are possible. All possible equivalent forms or ramifications of the invention are not intended in the present invention. It should 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 and scope of the invention.

Claims (127)

1. CLAIMS 1. A formulation for treating a patient for an inhaled neoplasm comprising: an effective amount of a vesicant and a pharmaceutically acceptable carrier, wherein the vesicant exhibits no substantial pulmonary toxicity.
2. 2. The formulation according to claim 1, wherein the vesicant comprises a moderate vesicant.
3. 3. The formulation according to claim 1, wherein the vesicant comprises paclitaxel and carboplatin.
4. The formulation according to claim 1, wherein the vesicant comprises: a non-encapsulated anticancer drug, wherein 0.2 ml of said drug was injected intradermally into rats, at the clinical concentration for parenteral use in humans: (a) the results are a lesion with an area of at least 20 mm2 fourteen days after said intradermal injection; and (b) at least 50% of the rats tested have this injury size.
5. 5. The formulation according to claim 1, wherein the vesicant comprises a severe vesicant.
6. The formulation according to claim 1, wherein the vesicant comprises a severe vesicant selected from the group comprising doxorubicin, vincristine, and vinorelbine.
7. 7. The formulation according to claim 1, wherein the neoplasm is a pulmonary neoplasm, a neoplasm of the head and neck, or other systemic neoplasm.
8. 8. The formulation according to claim 1, wherein said drug is in the form of a liquid, a powder, a liquid aerosol or a powder aerosol.
9. 9. The formulation according to claim 1, wherein said drug comprises tubulin inhibitors.
10. The formulation according to claim 1, wherein said drug comprises alkylating agents. eleven .
11. The formulation according to claim 1, wherein said drug comprises an anthracycline.
12. The formulation according to claim 1, wherein said anthracycline is selected from the group consisting of epirubicin, daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin and idarubicin.
13. The formulation according to claim 12, wherein when the doxorubicin is selected from said effective amount of the drug for animals is from about 2 to 90 mg / m2 and the dose for humans is from about 3 to 130 mg / m2, where both doses are based on the body surface area.
14. The formulation according to claim 1, wherein said drug is an alkaloid vinca.
15. 15. The formulation according to claim 14, wherein said alkaloid vinca is selected from the group consisting of vincristine, vinorelbine, vinorelbine, vindesine and vinblastine.
16. The formulation according to claim 15, wherein when the vincristine is selected, the dose for animals is about 0.06 to 2 mg / m2 and the dose for humans is about 0.1 to 3 mg / m2 and when selected vinorelbine, the dose for animals is about 1.3 to about 60 mg / m2 and the dose for humans is about 2 to 90 mg / m2, where all doses are based on body surface area.
17. The formulation according to claim 1, wherein said drug is a vesicant selected from the group consisting of mechlorethamine, mithramycin and dactinomycin.
18. 18. The formulation according to claim 1, wherein said drug is bisantrene.
19. 19. The formulation according to claim 1, wherein said drug is amsacrine.
20. The formulation according to claim 1, wherein said drug is a taxane. twenty-one .
21. The formulation according to claim 1, wherein said drug is paclitaxel.
22. The formulation according to claim 21, wherein wherein the dose for animals is from 6 to 90 mg / m2 and the dose for humans is from 10 to 400 mg / m, wherein both doses are based on the area superficial body 23.
23. A formulation for treating a patient having a neoplasm by inhalation comprising: (1) a safe and effective amount of an antineoplastic drug having a molecular weight above 350, which does not exhibit substantial pulmonary toxicity; and 24.
24. The formulation according to claim 23, wherein said neoplasm is a pulmonary neoplasm, a neoplasm of the head and neck, or a systemic neoplasm.
25. The formulation according to claim 23, wherein the drug is in the form of a liquid, a powder, a liquid aerosol, or a powder aerosol.
26. 26. The formulation according to claim 23, wherein the drug has a protein binding affinity of 25% or more.
27. 27. The formulation according to claim 26, wherein said drug has a protein binding affinity of 50% or more.
28. The formulation according to claim 23, wherein said drug has a molecular weight above 400.
29. 29. A formulation for treating a patient for a neoplasm by inhalation comprising: a safe and effective amount of a taxane in a an effective amount of vehicle comprising polyethylene glycol (PEG) and an alcohol.
30. 30. The formulation according to claim 29, further comprising an acid, said acid present in an amount effective to stabilize said taxane.
31. 31 The formulation according to claim 29, wherein said alcohol is ethanol.
32. 32. The formulation according to claim 29, wherein said acid is an organic acid.
33. 33. The formulation according to claim 29, wherein said acid is citric acid.
34. 34. The formulation according to claim 29, wherein said taxane comprises paclitaxel.
35. 35. The formulation according to claim 34, comprising about 8% to 40% polyethylene glycol, from about 90% to 60% alcohol and from about 0.01% to 2% acid.
36. 36. The formulation according to claim 35, wherein said safe and effective amount provides an animal dose of from about 6 to about 90 mg / m2 and a human dose of from about 10 to 400 mg / m2, wherein The dose is based on the body surface area.
37. 37. a formulation for treating a patient for a neoplasm by inhalation comprising: a safe and effective amount of a drug selected from the group consisting of carmustine, dacarbazine, melphalan, mercaptopurine, mitoxantrone, esorubicin, teniposide, aclacinomycin, plicamycin, streptozocin, and menogarilo; and a safe and effective amount of a pharmaceutically effective vehicle, wherein the drugs do not exhibit substantial lung toxicity.
38. 38. A formulation for treating a patient for an inhaled neoplasm comprising: a safe and effective amount of a drug selected from the group consisting of estramustine phosphate, geldanamycin, briostatin, suramin, carboxyamido-triazoles; onconase and SU 101 and its active metabolite SU20; and a safe and effective amount of a pharmaceutically effective carrier, wherein said drugs do not exhibit substantial lung toxicity. 39. A formulation for treating a patient for a neoplasm by inhalation comprising: a safe and effective amount of a drug selected from the group consisting of estramustine phosphate, geldanamycin, briostatin, suramin, carboxyamido-triazoles; onconase and SU 101 and its active metabolite SU20; and a safe and effective amount of a pharmaceutically effective vehicle, wherein the drugs do not exhibit substantial lung toxicity.
39. 39. A formulation for treating a patient for an inhaled neoplasm comprising: a safe and effective amount of etoposide and a DMA vehicle.
40. 40. The formulation according to claim 39, wherein. the formulation provides an animal dose of about 4.6 to 200 mg / m2 and a human dose of about 7 to about 300 mg / m2, wherein said doses are based on the body surface area.
41. 41 A formulation for treating a patient for a neoplasm by inhalation comprising a safe and effective amount of a microsuspension of 9-aminocamptothecin in an aqueous vehicle.
42. 42. The formulation according to claim 39, wherein the formulation provides an animal dose of approximately 2.6 to 10 mg / m2 and a human dose of approximately 0.04 to 15 mg / m2, wherein said doses are based on the body surface area.
43. 43. A formulation for treating a patient having a neoplasm comprising: administering said patient by inhalation; (1) an effective amount of highly toxic antineoplastic drug; and (2) an effective amount of a chemoprotectant wherein said chemoprotective reduces or eliminates toxic effects in the patient that are a result of administering highly toxic antineoplastic drugs.
44. 44. The formulation according to claim 43, wherein the chemoprevent reduces or eliminates systemic toxicity in said patient.
45. 45. The formulation according to claim 43, wherein the chemoprevent reduces or eliminates the toxicity in the respiratory tract in said patient.
46. 46. The formulation according to claim 43, wherein the chemoprotectant comprises dexrazoxane (ICRF-187), mesna (ORG-2766), etiofos (WR2721), or a mixture thereof.
47. 47. The formulation according to claim 43, wherein the chemoprevent is administered before, after or during the administration of said antineoplastic drug.
48. 48. The formulation according to claim 43, wherein the antineoplastic drug comprises a non-vesicant.
49. 49. The formulation according to claim 43, wherein the antineoplastic drug comprises a moderate vesicant.
50. 50. The formulation according to claim 43, wherein the antineoplastic drug comprises a severe vesicant.
51. 51 The formulation according to claim 43, wherein the antineoplastic drug comprises bleomycin.
52. 52. The formulation according to claim 43, wherein the antineoplastic drug comprises doxorubicin.
53. 53. The formulation according to claim 43, wherein the antineoplastic drug comprises mitomycin-C.
54. 54. A method for treating a patient having a neoplasm comprising: administering to said patient by inhalation, (1) an effective amount of a highly toxic antineoplastic drug; and (2) an effective amount of a chemoprotectant, wherein the chemoprevent reduces or eliminates the toxic effects in the patient which is a result of the administration of said highly toxic antineoplastic drug.
55. 55. The method according to claim 54, wherein the chemoprevent reduces or eliminates systemic toxicity in said patient.
56. 56. The method according to claim 54, wherein the chemoprevent reduces or eliminates the toxicity in the respiratory tract in said patient.
57. 57. The method according to claim 54, wherein the chemoprevent comprises dexrazoxane (ICRF-187), mesna (ORG-2766), etiofos (WR2721), or a mixture thereof.
58. 58. The method according to claim 54, wherein the chemoprevent is administered before, after or during administration of the antineoplastic drug.
59. 59. The method according to claim 54, wherein the antineoplastic drug comprises a non-vesicant.
60. 60. The method according to claim 54, wherein the antineoplastic drug comprises a moderate vesicant.
61. 61. The method according to claim 54, wherein the antineoplastic drug comprises a severe vesicant.
62. 62. The method according to claim 54, wherein the antineoplastic drug comprises bleomycin.
63. 63. The method according to claim 54, wherein the antineoplastic drug comprises doxorubicin.
64. 64. The method according to claim 54, wherein the antineoplastic drug comprises mitomycin-C.
65. 65. A method for treating a patient having a neoplasm comprising: administering a pharmaceutically effective amount of an antineoplastic drug not encapsulated to said patient by inhalation, the drug selected from the group consisting of antineoplastic drugs wherein when injected intradermally 0.2 mi of said drug to rats, at the clinical concentration for IV use in humans: (a) results in a lesion which is greater than 20 mm2 area fourteen days after said intradermal injection; and (b) at least 50% of the rats tested have these lesions.
66. 66. The method according to claim 65, wherein when said drug is doxorubicin or vinblastine sulfate, the drug is inhaled in the absence of perfluorocarbon.
67. 67. The method according to claim 65, wherein the neoplasm is a pulmonary neoplasm, a neoplasm of the head and neck, or other systemic neoplasm.
68. 68. The method according to claim 65, wherein the drug is inhaled as a liquid aerosol or as a powder aerosol.
69. 69. The method according to claim 65, wherein the patient is a mammal.
70. 70. The method according to claim 65, wherein the patient is a human being.
71. 71. The method according to claim 65, wherein the drug is an anthracycline selected from the group consisting of doxorubicin, daunorubicin, methoxymorpholinodoxorubicin, epirubicin, cyanomorpholinyl doxorubicin, and idarubicin.
72. 72. The method according to claim 65, wherein the drug is an alkaloid vinca.
73. 73. The method according to claim 65, wherein the drug is selected from the group consisting of vincristine, vinorelbine, vindesine and vinblastine.
74. 74. The method according to claim 65, wherein the drug is selected from the group consisting of mechlorethamine, mitramycin and dactinomycin.
75. 75. The method according to claim 65, wherein the drug comprises bisantrene.
76. 76. The method according to claim 65, wherein the drug comprises amsacrine.
77. 77. The method according to claim 65, wherein the drug comprises a taxane.
78. 78. The method according to claim 77, wherein the taxane comprises doxitaxel.
79. 79. The method according to claim 77, wherein the drug comprises paclitaxel.
80. 80. The method for treating a patient having a neoplasm comprising: administering an effective amount of a highly toxic non-encapsulated antineoplastic drug to a patient by inhalation, wherein the molecular weight of said drug is above 350, and said drug does not have substantial pulmonary toxicity.
81. 81 The method according to claim 80, wherein the neoplasm is a pulmonary neoplasm, a neoplasm of the head and neck, or a systemic neoplasm.
82. 82. The method according to claim 80, wherein the drug is inhaled as a liquid aerosol or as a powder aerosol.
83. 83. The method according to claim 80, wherein the drug has a protein binding affinity of 25% or more.
84. 84. The method according to claim 83, wherein the drug has a protein binding affinity of 50% or more.
85. 85. The method according to claim 80, wherein the drug is selected from the group comprising doxorubicin, epirubicin, daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin and idarubicin.
86. 86. The method according to claim 80, wherein the drug is an alkaloid vinca administered without the presence of a perfluorocarbon.
87. 87. The method according to claim 80, wherein the drug is selected from the group consisting of vincristine, vinorelbine, vindesine and vinblastine.
88. 88. The method according to claim 80, wherein the drug is mechlorethamine, mithramycin or dactinomycin.
89. 89. The method according to claim 80, wherein the drug is bisantrene or amsacrine.
90. 90. The method according to claim 80, wherein the drug is doxitaxel or paclitaxel.
91. 91 The method according to claim 80, wherein the patient is a mammal.
92. 92. The method according to claim 80, wherein the patient is a human being.
93. 93. A method for treating a patient for a neoplasm comprising: administering an effective amount of an antineoplastic drug to said patient by inhalation; and administering a pharmaceutically effective amount of the same and / or different anti-neoplastic drug to said patient parenterally.
94. 94. The method according to claim 93, wherein the patient is also treated by radiotherapy.
95. 95. The method according to claim 93, wherein the patient is also treated with immunotherapy.
96. 96. The method according to claim 93, wherein the patient is also treated with gene therapy.
97. 97. The method according to claim 93, wherein the patient is also administered chemoprotective drugs.
98. 98. The method according to claim 93, wherein said patient was also administered chemopreventive drugs.
99. 99. A method for treating a patient for a neoplasm comprising: administering an effective amount of an antineoplastic drug to said patient by inhalation; and administering an effective amount of the same and / or different antineoplastic drug to said patient by isolated organ perfusion.
100. 100. The method according to claim 99, wherein the patient is a mammal.
101. 101 The method according to claim 99, wherein the patient is a human being.
102. 102. The method according to claim 99, wherein the patient was also treated by radiotherapy.
103. 103. The method according to claim 99, wherein the patient is also treated by immunotherapy.
104. 104. The method according to claim 99, wherein the patient is also treated by gene therapy.
105. 105. The method according to claim 99, wherein the patient is also administered chemoprotective drugs.
106. 106. The method according to claim 99, wherein the patient was also administered chemopreventive drugs.
107. 107. A method for treating a patient for pulmonary neoplasm comprising: (1) selecting one or more effective antineoplastic drugs to treat said neoplasm and having a sufficient residence time in the pulmonary mucosa to be effective in the treatment of said pulmonary neoplasm; and (2) administering said drugs to said patient by inhalation in an unencapsulated form.
108. 108. The method according to claim 107, wherein when 0.2 ml of said drug or at least one of said drugs is injected intradermally into rats, at the clinical concentration for parenteral use in humans: A. a lesion results which is greater than 20 mm2 of area, fourteen days after said intradermal injection; and B. at least 50% percent of the treated rats have these lesions.
109. 109. The method according to claim 108, wherein said formulation results in a lesion that is greater than about 10 mm2 in area, 30 days after said intradermal injection; and at least about 50% of the rats tested have these fairly long-lasting injuries. 10.
110. The method according to claim 107, wherein the molecular weight of at least one of the selected drugs is above 350. 1 1 1.
111. The method according to claim 107, wherein said patient is a mammal.
112. The method according to claim 107, wherein said patient is a human being. 13.
113. A method of use, comprising the administration of one or more highly toxic anticancer drugs not encapsulated in a mammal by inhalation, wherein at least one of said drugs comprises a severe vesicant. 14.
114. An apparatus for treating a patient for a neoplasm by inhalation comprising: in combination a nebulizer and a formulation for treating a neoplasm comprising: (1) an anticancer drug not encapsulated, and (2) a vehicle pharmaceutically acceptable; wherein 0.2 ml of said formulation is injected intradermally into rats, at the clinical concentration for parenteral use in humans; (a) results in a lesion which is greater than about 20 mm2 in area fourteen days after said intradermal injection; and (b) at least 50% of the rats tested have these lesions. 15.
115. The apparatus according to claim 14, wherein the formulation results in a lesion that is greater than about 10 mm2 in area, 30 days after said intradermal injection; and at least about 50% of the rats tested have these long-lasting lesions. 16.
116. The apparatus according to claim 14, wherein the formulation further comprises an anthracycline. 17.
117. The apparatus according to claim 16, wherein the anthracycline is selected from the group consisting of epirubicin, daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin, and idarubicin. 18.
118. The apparatus according to claim 14, wherein the formulation further comprises an alkaloid vinca.
119. 119. The apparatus according to claim 18, wherein the alkaloid vinca is selected from the group consisting of vincristine, vinorelbine, vinorelbine, vindesine and vinblastine.
120. 120. The apparatus according to claim 14, wherein said formulation comprises a vesicant selected from the group consisting of mechlorethamine, mithramycin and dactinomycin.
121. 121. The apparatus according to claim 14, wherein said formulation further comprises bisantrene or amsacrine.
122. 122. The apparatus according to claim 14, wherein said formulation further comprises a taxane.
123. 123. The formulation according to claim 122, wherein the taxane is paclitaxel or doxitaxel.
124. 124. A mask for inhalation to administer aerosols to a patient comprising: a. means for covering the mouth and nose of said patient, having an open end and a closed end, the open end adapted to be placed over the mouth and nose of said patient; b. upper and lower holes in said closed end adapted to insert a nose outlet tube and a mouth inhalation tube; c. said nose outlet tube attached to said upper hole, adapted to accept exhaled breath from said patient's nose; d. a one-way valve in the nose tube adapted to allow exhalation but not inhalation; and. One inhalation tube of the mouth having an external and an internal end, partially inserted through the lower orifice, the inner end continuing at the end of the mouth of said patient, the end of the tube. inhalation is cut at an angle so that the lower portion extends further into the patient's mouth than in the upper portion and adapts to adjust the curvature of the posterior part in the patient's mouth; and f. A Y shaped adapter attached to the outer end of the mouth inhalation tube.
125. 125. The mask according to claim 124, further comprising a moderate vesicant present in the inhalation tube.
126. 126. The mask according to claim 124, further comprising a severe vesicant present in the inhalation tube.
127. 127. Any and all novel aspects or combination of aspects, described in the specification of this application.