TW201141539A - Medical aerosol formulation - Google Patents

Abstract

Disclosed herein is an aerosol formulation for use in a metered dose inhaler (MDI) for treating an allergic disease such as asthma. The formulation uses a combination of a non-cholrofluorocarbon (non-CFC) propellent, a co-solvant, and a surfactant to suspend, solubilize, and emulsify ribavirin into micronized particles for easy delivery to the respiratory tract and/or lung of a subject by oral or nasal inhalation in order to treat the allergic disease.

Description

201141539 VI. Description of the invention: [Technical field to which the invention pertains] The content of the invention is related to the field of pharmacy. In particular, this disclosure is not relevant for a quantitative spray (Me

Mm) aerosol formulation. This aerosol is equipped with the Rebavirin (10)^ tank age. (d) in having therapeutic asthma (previous technique)

In the treatment of various diseases including pneumonia, bronchial asthma and chronic lung obstruction, as well as various diseases such as pain management and hormonal treatment, it is a necessary treatment to deliver drugs to the lungs by inhalation. the way. Recently, it has been confirmed that a conventional anti-infective agent, ribavirin, can be effectively administered to an individual such as asthma, hay fever, bronchial asthma, allergic rhinitis, atopic dermatitis, and the like. Allergic diseases such as anaphylactic shock (see Chiang and Huang, WO 2007/104070). Therefore, there is an urgent need to develop a formulation of ribavirin containing ribavirin granules of varying size and in size, and these ribavirin granules can be administered by oral and/or nasal inhalation. In order to treat an allergic disease of a body, the present invention is a solution proposed for the above purpose, and the present invention proposes an aerosol formulation which comprises ribavirin particles having a size in the respirable range and these The microparticles can be incorporated into a dispersion comprising a propellant and a metered dose spray suitable for pressurization. For the application of the metered spray, the resulting aerosol formulation is subsequently filled into an aerosol can equipped with a 201141539 sputum trap. The user can dispense the formulation via an actuator to direct the formulation from the valve into the patient. SUMMARY OF THE INVENTION The present invention is a novel aerosol formulation that can be used in a quantitative spray (MDI), which can be used to treat an allergic disease of a body, particularly suffering from asthma, hay fever, Individuals with bronchial asthma, allergic nasal k, atopic dermatitis, and anaphylactic shock. The aerosol formulation comprises microparticles of one of the active agents in the respirable range (reSpirabie or inhaiabie) which can be delivered to an individual via a fluid carrier. Accordingly, a first aspect of the present disclosure is to provide a novel aerosol formulation that can be used in a metered spray (MDI). This aerosol formulation comprises about 1 to 1 Torr (1% by weight) of ribavirin; about 0.0001 to 15% (replacement %) of cosolvent; about 0.0001 to 1% (by weight) %) of a surfactant; and about 83 to 99% by weight of a non-chlorofluorocarbon (non-CFC) propellant. According to a particular embodiment of the present disclosure, the propellant of the non-fluoroalkane carbide is any of the following compounds: 丨山^·tetrafluoroethane (HFA-134a), 1,1,1,2,3,3, 3-heptafluoropropane (1^8-227) or a mixture thereof. In some embodiments, the propellant of the non-fluoroalkane carbide is ruthenium, osmium, iridium, 2-tetrafluoroethylene (HFA-134a). According to a particular embodiment of the present disclosure, the cosolvent is selected from the group consisting of propane, butane, n-pentane, isopentane, neopentyl, ethanol, isopropanol and propylene glycol. In certain instances, the cosolvent r r 4 201141539 is ethanol. According to the present disclosure, the surfactant is selected from the group consisting of sorbitol monolaurate (SPAN 2〇), sorbitol monooleate (SPAN 80), and Yamanashi. Alcohol trioleate (SPAN 85), polyoxyethylene sorbitan monolaurate (TWEEN 20), polyoxyethylene sorbitan monooleate (TWEEN 80), egg fat (EPIKURON 200), oil-based polyoxygen BS JI (BRJI 92), stearic acid-based polyoxyethylene oxime (brji 72), lauric acid-based polyoxyethylene ether (BRJI 30), block copolymer of oxyethylene and oxypropylene • (block cop〇lymer ), oleic acid, diethylene glycol dioleate, tetrahydrofuranyl oleate, ethyl oleate, isopropyl myristate, glyceryl oleate, glyceryl stearate, glycerol monolaurate, single Cis ricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol, propoxylated polyethylene glycol, diethylene glycol monoethyl ether, polyvinyl pyrrolidone (PVP), eucalyptus oil , corn oil, cotton oil, sunflower seed oil and combinations thereof. In one example, the surfactant is less than about 1% (wt%) polyethylene glycol. In another example, the surfactant 疋 is composed of about 5% by weight of polyethylene glycol and about 5% by weight of oleic acid. The second aspect of the present disclosure is to provide a quantitative spray comprising the aerosol formulation of the present invention as described above. These and other features of the present disclosure will be apparent from the following detailed description. The above summary and the following detailed description are merely illustrative of the disclosure and are not intended to limit the scope of the disclosure. 201141539 [Embodiment] The following disclosure relates to an aerosol formulation; in particular, to an aerosol formulation that can be used for Metered dose inhaler (MDI). This aerosol formulation is characterized by the inclusion of Reba Ribavirin is the only active agent to treat allergic diseases such as asthma, hay fever, bronchial asthma, allergic rhinitis, atopic dermatitis and anaphylactic shock. In accordance with an embodiment of the present disclosure, an aerosol formulation useful for MDI φ is provided. The aerosol formulation comprises from about 0.000 1 to 1% by weight of ribavirin; from about 0.0001 to 15% by weight of the cosolvent; from about 0.0001 to 1% by weight of the surfactant And a propellant of about 83 to (weight I%) non-fluorine gas-fired carbide (n〇n_chl〇r〇flu〇r〇carb〇n, non-CFC). In the past, ribavirin was used as an anti-infective agent for the treatment of viral attenuation. However, it has recently been stated that the use of ribavirin alone can effectively treat allergic diseases, including, but not limited to,

Asthma, hay fever, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock (see Chiang (4),: Xie Chuan side). The purpose of the pharmaceutical formulation of the present invention is to enable the pharmaceutical formulation to be inhaled into the lungs by the patient, and therefore the drug must be micronized so that each effective dose of the drug is in the form of microparticles. Generally speaking, the average diameter of each drug particle is preferably about 1 to "between about 3 m", so that the particles can be inhaled to the healthy time channel (4). Therapeutic 201141539 is available in an effective dosage form, that is to say, each dose administered via the oral cavity or the nasal cavity is in the form of a dispersion or an aerosol, and can achieve the desired therapeutic effect; preferably via one dose or multiple doses. To achieve the desired therapeutic effect. Typically, a therapeutic valve is administered via a gas transfer adapter (also known as an actuator) using a conventional valve, such as a metered doser valve. In the formulation of the present invention, the formulation contains The amount of the drug or ribavirin is about 0.0001 to 1 〇 / 〇 (% by weight), preferably about 〇 to 8% (replacement %), more preferably about 〇 5% (% by weight) - In the present disclosure, the aerosol formulation is prepared by micronizing a live drug (ie, ribavirin) to form an average diameter of between about 1 and about MW. Granules; pick the appropriate size of the drug granules so that the formula contains at least More than about 9% by weight of the ribavirin microparticles having an average diameter of about u1 G m, for example, having an average diameter of about 9 to 92, 93, 94, 95, 96, 97' 98, 99 or 100%, about 1 to 1〇111 ribavirin microparticles; the selected ribavirin microparticles are mixed with other ingredients (such as 'cosolvent, surfactant and propellant); The material is sealed in a sealed can. The average diameter of the desired ribavirin microparticles is below 1 Gm, preferably S is between about 1 and 6 m, more preferably about 3 m. Reduced ribavirin particle diameter The purpose of the invention is to enable a body to inhale the pharmaceutical formulation of the present invention, and to converge the ribavirin particles into the lungs for the purpose of delivering the drug-carrying substance. Knowing ways to reduce the head handle of the Rebailin granules, such as by milling or micronization, etc.

The hazelnut reduces the particle size. Particle H 7 201141539 Γ: _ ΓΠ 技术 技术 ΓΠ 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术 技术Mechanical cutting is performed by moving parts inside the mill (eg, plates, knives, and abrasive parts). Alternatively, in addition to the polishing portion of each of the knocking drugs, the various sizes of the drug can be made smaller or smaller than the closed miller i. The rotation or the rotation of the chamber can be used to increase the diameter of the drug particles. Some mills, for example! 2 " I ϋ (fluld energy miH) ^ ^ ^ ^ ^ ^ (air jet miU) ^ Qiu, can make the bulk of the drug in the chamber and the internal rate of the mill: the impact of the suede, resulting in crushing effect. - Once the desired p is reached, the grinding can be stopped and the drug of the desired size can be recovered. == The granules can be granulated by grinding the dry powder of ribavirin, and the appropriate average size, for example, between m, 疋, · "Between 1 and 6 m, preferably about 3 m, the above d size is suitable for inhaling the size of the respiratory tract or the lungs. Because of the body, the range of the diameter of the monthly positive drug particles is higher than the above. The range (including better or better) is wide. It is important to know that although most of the particle diameter will fall within the smaller range of the desired range, the particle diameter will fall within the small range of the desired particle size. The proportion falling within the range of desire is more than 90%. For example, the average diameter of particles of about 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% will fall within the above-mentioned range of requirements. Depending on the specific needs, 201141539 may further reduce the diameter of the drug particles by other means such as division, homogenization and/or granulation. Any of the above techniques may be used alone or in combination with at least two of them. In terms of The drug is ground and homogenized, and then passed through to obtain ribavirin particles having an average diameter of desired, for example, an average diameter of about 3 m. In order to maximize the function of an aerosol formulation, it must be used in combination in the formulation. Appropriate commercially available surfactants, co-solvents and propellants to prevent formulation

The active drug (ie, micronized ribavirin) is too fast after the disturbance, so that the patient needs to apply a second dose to achieve a therapeutically effective dose. Therefore, the aerosol formulation of the present invention contains extremely uniform dispersion. Micronized ribavirin particles that are substantially free-flowing such that they can be easily dispersed in an inhalation device (eg, MDI); and then the patient inhales the lungs through the mouth or nasal cavity Towels. Therefore, the above-mentioned micronized ribavirin particle size is basically a size suitable for inhaling into the lungs. In general, the aerosol formulation of the present invention can be made by combining the following: (1) - an effective amount of micronized ribavirin granules prepared in the manner described above, which is sufficient to provide multiple therapeutically effective doses of thunder Bavirin particles; (2) an effective amount of a co-solvent 'this amount is sufficient to help disperse the above-mentioned micronized ribavirin particles to form a dispersion; (3) an effective amount of a surfactant, To stabilize the formulation; and (4) an effective amount of fluid or propellant to advance the multiple doses, for example, from a sealed can. Suitable cosolvents which can be used in the aerosol formulation of the present invention include, but are not limited to, propane, butane, n-pentane, isopentane, neopentane, ethanol, isoinomer. 9 201141539 Alcohol and propylene glycol. The aerosol formulation of the present invention preferably comprises from about 10 to 15% by weight of a cosolvent, more preferably from about 10 to 13% by weight of a cosolvent, and most preferably Contains about 10% (% by weight) of the cosolvent. In one example, the formulation contains about 10% (by weight) ethanol as the cosolvent. ^ Surfactants are commonly used to stabilize an aerosol formulation. Suitable surfactants include, but are not limited to, oils derived from natural sources such as corn oil, olive oil, cottonseed oil, sunflower seed oil; SPAN series of surfactants such as sorbitol monolaurate (SPAN 2) 〇), sorbitol monooleate (SPAN 80), sorbitol trioleate (spAN 85); polyoxyethylene sorbitan monolaurate (TWEEN 20), polyoxyethylene sorbitan monooleate (TWEEN 80); lecithin (EPIKURON 200); BRJI series of surfactants, such as oil-based polyoxyethylene ether (BRJI 92), stearic acid-based polyoxyethylene ether (BRJI72), lauric acid-based polyoxyethylene ether (BRJI3 〇); oxyethylene and oxypropylene embedded #block copolymer; oleic acid; diethylene glycol / by 酉文自日' tetrahydromanate oleate; ethyl oleate; Isopropyl vinegar; 1 ^ glycerin vinegar; glyceryl stearate; glycerol monolaurate; mono succinimide glycerol, cetyl alcohol; stearyl alcohol; polyethylene glycol; propoxylated poly '-monool monoethyl ether; polyvinylpyrrolidone (pvp); and octane and 5. It is to be noted that two or more of the above surfactants may be used in combination in the aerosol formulation of Shifa. Those skilled in the art can readily find suitable surfactant combinations without undue experimentation and use in the formulations of the present invention to preferably comprise less than about 1% by weight of the interface. (4) For example, about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 201141539 0.1 or 0.01 (% by weight) of a surfactant. In one example, the interfacial surfactant is polyethylene glycol. In another example, the formulations of the present invention comprise an interfacial active agent comprising from about 5% by weight polyethylene glycol to about 0.5 Å. (Heavy ί /ί)) is a combination of oleic acid.

The low carbon number fluorinated alkane, particularly the non-fluorofluoroalkane carbide gas, is the propellant gas (also referred to herein as a propellant) which is most suitable for use in the present invention. These propellant gases are typically employed in the formulation in an amount of at least about 83% by weight, such as between about 83% (% by weight) and 99% (% by weight), such as 83, 84, 85, 86, 87, 88, 89. , 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% (by weight. More preferably, these propellant gases are used in the formulation at levels of from 85% (% by weight) to 95% (% by weight). Optimum is about 9〇% (Heavily 4) Examples of non-fluorine gas slagging gas include, but are not limited to, U,1,2-tetrafluoroethane (HFA-134a), ^^^heptafluoropropane ( HFA - 2 2 7 ) and mixtures thereof. In the formulation of the present invention, the agent is preferably a non-gas cylinder carbide propellant comprising between about 83% (% by weight) and 99% (% by weight); more preferably Included from about 85% (% by weight) to 95% (% by weight) of the non-hydrocarbon sulphonate propellant; preferably comprising about 9% by weight of non-HCFC propellant. In some embodiments, the non-fluoroalkane carbide adduct is 1,1,1,2-tetrafluoroethane (HFA_134a). In other examples, the non-fluorochlorocarbonate propellant is mm]• Heptafluoropropyl " (HFA-227). Composition in the formulation of the present invention The micronized ribavirin particles, cosolvents, surfactants, and propellants can be dispersed using conventional agitators or homogenizers, or by shaking, or ultrasonic energy. Γ f 11 201141539 Lee: valve-to, type of transfer, or pressurized filling method, the transfer of a large number of formula into a smaller, individual aerosol container can be used with a wide range of aerosol cans Preferably, an aerosol canister equipped with a metered spray valve delivers the formulation of the present invention., can, & delivers the formulation of the present invention to the respiratory tract and/or lung by mouth inhalation. U can be achieved by inhaling the formulation of the present invention. Therapeutic effects of diseases such as asthma, hay fever, bronchial asthma, allergic rhinitis,

Position dermatitis and anaphylactic shock. The formula can also be transmitted via nasal inhalation to treat any of the above diseases, including, but not limited to, 虱°, pulverized fever, bronchial asthma, allergic rhinitis, atopic dermatitis and Allergic shock 0 month or otherwise in this article and accompanying the scope of the request _ a (, '', ''catch'') or the (''comparable to 〇) are required to know unless otherwise specified, the singular The wording, the plural form, the embodiment and the proper noun are used to illustrate the content of the invention, and the disclosure is not intended to limit the disclosure. The disclosure is also not specifically disclosed herein. Other embodiments that can be easily inferred by a person skilled in the art after reading this disclosure. a Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, anything similar to what is described Or equivalent methods and materials can be used in the method of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only. As mentioned in this application, all references are The present invention is incorporated by reference to the entire disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of The actual data obtained by the present invention differs from the data disclosed in the present specification by the individual implementation conditions. The following embodiments are used to clarify the specific aspects of the present disclosure. The present disclosure is known and understood by those skilled in the art, but the scope of the disclosure is not limited to these embodiments. EXAMPLES Example 1 Example of Jet Grinding Rebecca Rebecca Forest is from Archimica (〇rigg〇, Italy) uses a jet mill (JET MILL® MC-50D) to micronize ribavirin. For each milling, approximately 60 grams of drug is used and aerobic particle size analyzer (Aerodymanic Particle SiZer) 3225, USA) to test and analyze the particle size of each particle after grinding to determine the size distribution range of the polished ribavirin particles after grinding. More than 9〇% of the ungrounded Rabavirin particles have an average diameter of less than about 29.6 + ? m; more than 90% of the average diameter of the micronized Rabavirin particles is less than about 5.3 ± 0.3 m; and the average diameter of the micronized ribavirin particles is about 3.4 ± 0.1 m; and the yield of ribavirin after passing through the jet mill is about 72%. The micronized ribavirin granules were used to make an aerosol formulation and mixed with 7.5 grams of polyethylene glycol 4 (PEG 400) and 170.4 grams of ethanol for about 10 minutes. 75 grams of the example was added. The micronized 窜13 201141539 Bawalin granules into this PEG 400/ethanol mixture and continue to give up mixing for about 20 minutes' followed by ultrasonic shock for about 10 minutes. Next, the obtained ribavirin suspension was fed into the Iprocomsa trap at a rate of about 300 rpm, and then about 1532.4 grams of HFA-134a propellant was fed and the resulting mixture was formed. To fill 120 bottles of sealed cans to form the desired aerosol formulation. The resulting aerosol formulation comprises a weight ratio of about 〇. 5 : 〇·5 : 10 : 90 of ribavirin: PEG 400: ethanol: HFA-134a. Examples 3 to 16 The aerosol formulations of Examples 3 to 16 were prepared in accordance with the compositional ratios of Examples 3 to 16 in Table 1 below, and in accordance with the method disclosed in Example 2. Comparative Examples 1 to 4 According to the composition ratio of Comparative Examples 1-4 in Table 1 below, and in comparison with the method disclosed in Example 2, a comparative implementation was prepared except that no surfactant and/or co-solvent were used. The aerosol formulation of Examples 1-4. • Table 1 Real composition (weight ratio) RB V PEG oleic acid PVP SPAN EtOH HFA-1 34a 14 201141539

Example 400 85 Example 2 0.5 0.5 10 90 Example 3 0.5 0.05 10 90 Real 0.5 1 - - 10 90 15 201141539

Example 4 Example 5 0.5 0.25 0.25 10 90 Example 6 0.5 0.5 10 90 16 201141539

Example 7 0.5 1.0 10 90 Example 8 0.5 0.05 10 90 Example 0.5 0.125 0.125 10 90 17 201141539

9 Example 10 0.5 0.45 0.05 10 90 Example 11 0.5 0.45 0.05 10 90 Implementation 0.5 0.45 0.05 10 90 18 201141539

Example 12 Example 13 0.5 0.45 0.05 10 90 Example 14 0.5 0.45 0.05 10 90 Real 0.5 - 0.05 10 90 201141539 Example 15 Example 16 Comparative implementation 0.5 0.5 0.05 10 90 1 00 20 201141539 Example Comparative Example 2 Comparatively practical 0.5 0.5 10 15 90 85 21 201141539

Example 3 Comparative Example 4 0.5 20 80 Note: RBV represents the micronized ribavirin granules according to the method described in Example 1 according to the MDI/DPI guidelines issued by the US Food and Drug Administration (FDA) in 1998 or Is the test disclosed in the Inspiratory and Nasal Pharmaceutical Products 22 201141539 f issued by the European Medicines Agency (EMEA) in 2006 (4), and is equipped with the aerosol formulation and equipped with a -quantitative aerosol valve The sealed cans were tested for uniformity of the transfer dose. The test results showed that the total of 10 doses did not exceed the mean value of 250 g / puff soil 15% or 212.5 - 287. $ g / mouth. Other Embodiments Although the present disclosure has been disclosed in the above embodiments, it is not intended to limit the disclosure, and any person skilled in the art can make various changes without departing from the spirit and scope of the disclosure. Retouching, the scope of protection of this disclosure is subject to the definition of the scope of the patent application. [Simple diagram description] None [Main component symbol description] None

Claims (1)

201141539 VII. Patent application scope: 1. An aerosol formulation for Metered dose inhaler (MDI), comprising: about 0.000 1 to 1% (% by weight) of ribavirin; a cosolvent of from about 0.001 to about 15% by weight; a surfactant of from about 0.001 to about 1% by weight; and a non-compartment of from about 8.3 to 9% by weight A propellant of non-chlorofluorocarbon (non-CFC). 2. The aerosol formulation of claim 1 wherein the non-fluorochlorocarbonate propellant is any one of the following compounds: 1, 1, 1, 2-tetrafluoroethane (HFA-1 34a), 1 , 1,1,2,3,3,3-heptafluoropropane (1^-man-227) or a mixture thereof. 3. The aerosol formulation of claim 2, wherein the non-fluoroalkane carbide propellant is 1,1,1,2-tetrafluoroethane (HFA-13 4a). 4. The aerosol formulation of claim 1 wherein the cosolvent is selected from the group consisting of propane, butane, n-pentane, isopentane, neopentane, and r 24 201141539 Alcohol, isopropanol and propylene glycol. 5. The aerosol formulation of claim 1 wherein the surfactant is selected from the group consisting of: sorbitol monolaurate, sorbitan monooleate, sorbitol trioleate , polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, lecithin, oil-based polyoxyethylene ether, stearic acid polyoxyethylene ether, lauric acid polyoxyethylene ether, oxyethylene Block copolymer with oxypropylene, oleic acid, diethylene glycol dioleate, tetrahydrofuranyl oleate, oleic acid, sodium sulfonate, oleic acid glycerin , stearic acid glycerin S, monolauric acid glyceride, monocis ricinoleic acid glycerin S, recorded alcohol, stearyl alcohol, polyethylene glycol, propoxylated polyethylene glycol, diethylene glycol Monoethyl ether, polyvinylpyrrolidone (PVP), olive oil, corn oil, cottonseed oil, sunflower seed oil, and combinations thereof. 6. The aerosol formulation of claim 5 wherein the surfactant is polyethylene glycol. 7. The aerosol formulation of claim 5 wherein the surfactant is a combination of polyethylene glycol and oleic acid and is present in the formulation in an amount of about 0.5% by weight, respectively. 25 201141539 8. A quantitative spray comprising the aerosol formulation of claim 1. 9. The metered spray of claim 8, wherein the non-fluoroalkane carbide propellant is any one of the following compounds: 1,1,1,2-tetrafluoroethane (HFA-1 34a), 1,1,1,2,3,3,3-heptafluoropropane (11-8-227) or a mixture thereof. 10. The metered spray of claim 9, wherein the non-fluorochlorocarbonate propellant is 1,1,1,2-tetrafluoroethane (HFA-1344). 11. The metered spray of claim 8 wherein the cosolvent is selected from the group consisting of propane, butane, n-pentane, isopentane, neopentane, B. Alcohol, isopropanol and propylene glycol. 12. The metered spray of claim 81 wherein the surfactant is selected from the group consisting of sorbitol monolaurate, sorbitan monooleate, sorbitol trioleate Acid ester, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, lecithin, oil-based polyoxyethylene ether, stearic acid polyoxyethylene ether, lauric acid polyoxyethylene ether , oxyethylene and oxypropylene 26 201141539 block copolymer, oleic acid, ethylene glycol dioleate, tetrahydrofuranyl oleate, ethyl acetate, isopropyl myristate, glyceryl oleate , 酸酸酸酉, lauric acid glycerin, monocis glycerol S, succinyl alcohol, octadecanol, polyethylene glycol propoxylated polyethylene glycol, diethylene glycol single Ethyl ether polyvinylpyrrolidone (PVP), eucalyptus oil, eucalyptus oil, cottonseed oil, sunflower seed oil, and combinations thereof. 13. The metered spray of claim 12, wherein the surfactant is Polyethylene glycol. 14. The metered spray of claim 13 wherein the surfactant is a combination of polyethylene glycol and oleic acid and the amount of the formulation is about 0.5% by weight, respectively. 〇界界 27