JPH05507090A - Direct spray-dried drug/lipid powder compositions - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention provides a method for dispensing drugs by inhalation, in particular a metered dose of 800 mg for use by inhalation. 2).

Bart 1ett, G, R, J, Biol, Chem, 234:455 (1959).

Fisher, K., edited by Gary D., Christian References in Cal Chemistry 14th edition.

McGurk, J, G, et al. UK Patent Application iGB 2145107 A <1 985).

Leigh, S., European Patent No. 0158441 (191116).

PCT Application No. 11108610171 of Carman-Eakin, B., et al. No. 4 (1986).

McGurk, J, G, et al., UK Patent No. 2170815A (1911 18).

Leigh, S., PCT Application No. 87107502 (1987).

Radhakrishnan, R. et al., U.S. Pat. No. 4.895.719 (1 990).

The advantage of inhalation in the treatment of It is. The therapeutic effect is rapid compared to other means of administration such as intramuscular and oral routes. Speed of exit is also a related advantage. Easily destroyed in the gastrointestinal tract or orally For drugs that cannot be administered manually, inhalation is preferable to intravenous or intramuscular injection for various reasons. Delicious. Other drugs whose primary drug action is systemic, such as nitroglycerin Agents can also be effectively administered by inhalation.

Several methods are known for administering drugs by inhalation. That is, the drug is manufactured. This method involves forming a mist of fine particles by dissolving it in a suitable solvent.

Solutions of the drug may be prepared by pneumatic or ultrasonic nebulizers, or more conveniently by Can be aerosolized by a self-contained nebulizer containing a pressurized fluorocarbon propellant .

Inhalation of an aerosol mist means breathing in a respiratory hemist through the mouth or nose. When the drug-containing aerosol particles enter the upper nasopharyngeal region, bronchial region, and lung region, act to attach to various parts of the respiratory tract, including the In the latter area, drugs is quickly absorbed into the bloodstream and has the opportunity to act systemically.

The drug may be prepared as a dry powder or as a micronized suspension in a suitable carrier solvent. Inhalation systems for dosing in particulate form are also known in the prior art. typically medicine The agent is a water-soluble compound suspended in ultrafine powder form in a fluorocarbon-type propellant solvent. Ru. After aerosolization, most of the propellant solvent is lost through flash evaporation and the Based on the fact that In such systems, the drug becomes available quickly and leaves no place for attachment in the lungs. In some cases, it is absorbed systemically at the site of attachment. This allows the drug to be absorbed and utilized quickly. The effect of the drug is relatively short-lived and often particularly desirable, especially for drugs characterized by dosing. Each drug is safe to administer if it has no systemic side effects. A related problem is that quantities are limited. This problem caused many notable heart palpitations. This is indicated by the resulting β2-adrenergic bronchodilator. These drugs are Even at relatively low doses, the drug's stimulatory effects on the heart and side effects such as dizziness and insomnia can be suppressed. The effect is bothersome to the patient. Furthermore, ultrafine particles can irritate the respiratory tract.

Furthermore, in recent years, liposomes have been developed to deliver drugs to the respiratory tract in the form of liposomes. A soma inhalation system was proposed. British Interpatent No. GB 2.1.45.107A , the aqueous solution and the organic solvent phase solution in which the lipid component is dissolved are combined under pressure and mixed. An aerosol device that passes the compound through a nozzle to form aerosolized liposomes. Are listed. European Patent No. 0.158.441 states that water/solubilized lipid/ether The formation of aerosolized liposomes from ethanol mixtures is disclosed. PC No. 8,610,1714 discloses that lipid droplets are transferred to a volatile liquid carrier. (which is a solvent for phospholipids) has been proposed. Aqueous table with wet droplets Liposomes are formed upon contact with a surface. British Patent EB Otsu No. 170.815 To do this, an aqueous solution is emulsified in a propellant solvent in which lipids are dissolved, and then the solution is released from a spray nozzle. Coated with lipids that form liposomes when sprayed and in contact with moist surfaces A system is described that forms liquid droplets. PCT application no. 87107502 No. 1, in which at least one membrane lipid is partially dissolved or dispersed. propellant solvents and biologically active compounds that are insoluble in the solvent; is listed. All these methods have high drug encapsulation when rehydrating one It has been taught to produce drug/lipid powders effective to form liposomes at Not yet.

Furthermore, the concentration and size of liposomes formed by prior art methods, and the The % uptake of drug in the system depends on temperature and humidity conditions, degree of solvent miscibility, and system will vary from dose to dose depending on the total and relative amounts of solvent components present. cormorant. Therefore, it is difficult to adapt each of these systems to metered dose dosing. Will. This is because reproducible amounts of drug encapsulated in liposomes are required. This is because that. On the other hand, the direct spray-dried drug/lipid powder of the present invention can be precisely weighed This is a convenient and effective method for administering the drug.

prepares an aqueous solution containing a water-soluble drug that is free of phosphate buffer salts, and The method includes preparing an ethanol solution containing a substance. These two solutions are then mixed into approx. Mix in a ratio of 1:1 to 5:1 ethanol:water (w/w). It is blended so that the total body weight is about 3 to 4% (w/v). Then this mixture Spray dry and collect the resulting dry particle powder.

The above (Method D) uses albuteral sulfate, ehydrin sulfate, Idoline Sulfate, Isoetaline Hydrochloride, Isoetaline Mesylate, Isoprop rotanol hydrochloride, isoproteranol sulfate, metaproteranol ruphate, terbutaline sulfate, procaterol, and bitolterol Mesylate, Atropine Methyl Nitrate, Cromolyn Sodium, Proplana rolls, fluorosolidides, ibuprofin, gentamicin, tovelmicin, PE Ntamidine, Veningin, Theophylline, Pleomicin, Etoposide, Captop Rilu, n-acetylcysteine, verapamil, calcitonin, atriopbutin , alpha-1 antitrypsin, interferon, oxytocin, pap pressin, Insulin, interleukin-2, superoxide dismutase, tissue protein Lasminogen activator, plasma factor 8, epidermal growth factor, tumor necrosis factor, granulocytes/large phagocyte colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor , pulmonary surfactant protein, and various water-soluble drugs including ribocortin. can be used to produce drug/lipid powder compositions.

Ethanol solutions containing lipids must contain at least one type of membrane-forming lipid. No. Typical lipids used in the powders of the present invention include the following lipids and similar lipids: This includes substances and derivatives. Phosphatidylcholine, phosphatidylglycerol , phosphatidic acid, phosphatidylinositol, phosphatidylethanol amines, phosphatidylserine, sphingomyelin, and cholesterol.

Representative analogs and derivatives of these lipids are shown in Table 1.

A preferred embodiment of the invention is a phosphatidyl glycerol and α-tocopherol in a weight ratio of about 167:15:0.1. Use an ethanol solution containing

The method of the invention also includes the use of agents such as "Freon" to solubilize lipids. Other organic solvents can be used, as well as non-film-forming lipids such as cholesterol. Contains vines.

The drug/lipid powder compositions of the present invention are packaged in packets containing a selected dosage of drug. Mounted.

There are three methods. In the first method, powder particles of the drug/lipid composition are suspended in a fluorocarbon propellant that does not solubilize the particles. Suspension is pressurized A selected amount of the suspension is inhaled by the user. Exclude from canister in aerosolized state. In the second and third methods The drug/lipid powder particles are mixed into water, each containing a metered dose of drug in the powder. Provided as a single-volume packet, the user inhales the air using a propellant or air stream. The particles are released from the packet while being carried by Dosing these drugs by inhalation The method is described in commonly owned U.S. Pat. No. 4,8, which is also incorporated herein by reference. No. 95.719.

administering a selected dose of the drug/lipid powder composition of the invention via the respiratory tract; A number of relatively portable and convenient devices are also described in the present disclosure. .

FIG. In this device, the powder of the composition is The powder is entrained in the airflow created in the passageway. is supported within the air passageway of the dispensing device.

Figure 2 shows albutyrol versus amount of rehydration using directly spray-dried powder. Figure 2 shows data regarding sulfate encapsulation.

Figure 3 shows the log (%) of the amount of water used for rewatering directly spray-dried powder. Figure 3 shows the linear regression line data for (Envelopment).

Figure 4 shows the results in guinea pigs after administering a metered dose of aerosol. Effect of spray-dried liposome-encapsulated on respiratory tract tolerance to histamine Effects of albutyrol sulfate and Provent il (trade name) Show comparison.

This composition produces (a) scales that form a fine particle size upon spray drying; (b) dehydration or (C) be stable upon storage in propellant suspension; (C) be stable upon rehydration of the composition; (d) drug entrapment rate in posomes is high; and (d) drug during administration to the respiratory tract. The ability to select kinetic behavior, including: It is necessary to enrich the quality and then spray dry the liposome suspension (e.g. See U.S. Pat. No. 4,895,719). The present invention pre-prepares liposomal drug suspensions. It has the important advantage that it does not need to be formed.

Egg phosphatidylcholine EPCO-15 to -7 dilauriloyl phosphatidyl Choline (C12:0) 0LPCO-1,8 simiristoylphosphatidylcoli (C14:0) DMPC023 Dipalmitoylphosphatidylcholine (C1 6:0) C041 distearoyl phosphatidylcholine (C18:0) 03PCO551-Myristoyl-2-balmitoyl phosphatidyl MPPC 027 Corin (C14:0.16:0) 1-Valmitoyl-2-myristoylphosphatidyl PMPCO35 Choline ( C12:0.14:0) l-Valmitoyl-2-stearoylphosphatidyl PSPC044 Choline ( [1620, 18:0) l-stearoyl-2-balmitoyl phosphatidyl 5PPC047 Choline ( C18:0.16:O) Dioleoylphosphatidylcholine (C18:l) DOPCO-22 Shilauri Leroylphosphatidylgly7ol DLPG-14 Similistoylphosphathi Dylglycerol DMPG-123 dipalmitoylphosphatidylglycero DPPG-141 distearoylphosphatidylglycerol SP G-155 Dioleoylphosphatidylglycerol DOPG-1-18 Simyristoylphosphatidic acid DMPA-151 Simyristoylphospha Tidic acid DMPA -245 dipalmitoylphosphatidic acid DPPA - 167 Dipalmitoylphosphatidic acid DPPA -258 Similistoylphosphatidic acid Suphatidylethanolamine [1MPE-50 dipalmitoyl phosphatidyl ethanolamine DPPE-60 cimilistoylphosphatidylserine RoMPS-38 dipalmitoylphosphatidylserine opps-si brain phos Fatidylserine BPS -6~8° Brain Sphingomyelin BSP 0 3 2 dipalmitoylsphingomyelin DPSP O41 distearoylsphingomyelin Ngomyerin 0SSP 057 The only lipid component used in the method of the present invention The requirement is that the lipids form membranes in aqueous solution. Typical to the invention The lipids used are egg phosphatidylcholine (EPC) and egg phosphatidylcholine (EPC). It is ruglycerol (EPG). Many other membrane-forming lipids are also used alone or in combination. The vines are used in the present invention. Examples of such lipids are shown in Table 1. Together with membrane-forming lipids Additionally, other lipid components such as cholesterol are also used in the formulation of drug/lipid compositions. I can do it. Generally, cholesterol is a component of the present invention that primarily contains saturated phospholipid components. Has a fluidizing effect on rehydrated liposomes. Specific lipid composition of liposomes affects the rate of drug release in the respiratory tract (U.S. patent of the same owner). No. 4,895.719).

The directly spray-dried drug/lipid compositions of the present invention also contain the antioxidant alpha-tamine. Contains various drug protection or lipid body I agents such as copherol. they are typical Generally speaking, it accounts for about 0.0% of the total fat. Contained in a molar ratio of 1 to 2.0 mol%.

A typical formulation of the present invention consists of partially hydrogenated EPC in a molar ratio of 55:40:5:0.1. :Cholesterol:EPG:α-tocopherol (9 cases 1). Cholestero The oil was omitted from the formulation of the present invention (Example 3). Furthermore, a stand-alone system such as EPC Lipids have also been effectively used as the sole lipid component of the drug/lipid compositions of the present invention.

The lipid components of the present invention completely solubilize them and provide a transparent solution when mixed with an aqueous solution. Combined in a solvent to form a solution. Ethanol is particularly useful in this regard. . Ethanol is used as the main solvent in all examples. some examples In (Examples 1 and 2), a small amount of “ Freon 11" (CC1, F) was used. Although a clear solution is desirable, ( i) the lipid components are solubilized; (ii) they are ready for the spray drying process; that the liquid is free-flowing when used as a solution; and (iii) the supply line It is most important that there are no solid precipitates.

As defined herein, a "drug" has a site of action within the respiratory tract or Any pharmaceutically active substance that is therapeutically active when absorbed systemically from the haustorial organs This means that it contains certain drugs. Such drugs include antibiotics, peptide hormones, drugs, enzymes, enzyme inhibitors, anticancer drugs, bronchodilators, allergens, and antihistamines. Includes

The most important class of agents used in this invention is primarily separated into the aqueous phase of a water/oil two-phase system. It is a water-soluble drug that tends to be administered. In particular, this type of drug has a lipophilic bilayer is preferentially distributed into the aqueous phase inside the liposome from the tube part (1-1a s e>). There is a tendency to This class of drugs includes albuteral (salbutamol) sulfate. , ehuidrine sulfate, ehuidrine sulfate, isoetaline hydrochloride Salt, Isoetaline Mesylate, Isoproteranol Hydrochloride, Isoproteranol sulfate, metaproteranol sulfate, terbutaline sulfate, Procaterol and bitolterol mesylate, atropine methyl nitrate , Cromolyn Sodium, Propranalol, Fluoroisolide, Ibuprofi gentamicin, tovermicin, pentamidine, penicillin, theophylline, Pleomicin, etoposide, captogril, n-acetylcysteine, and vera Relatively small liposome-permeable drugs such as Pamil: and peptide hormones, enzyme blocker, apolipoprotein, and calcitonin, atriopbutin, α -1 antitrypsin (protease inhibitor), interferon, oxytocin Pap pressin, insulin, interleukin-2, superoxide Smutase, tissue plasminogen activator (TPA), plasma factor 8, epidermal growth factor child, tumor necrosis factor, granulocyte/macrophage colony-stimulating factor, granulocyte colony-stimulating factor to children, macrophage colony-stimulating factor, lung surfactant protein, and ribocortin. Relatively large liposome-impermeable drugs such as high molecular weight hydrocarbons Contains agents.

The selected drug is dissolved in an aqueous solution at a specific concentration. Generally, drug concentrations are Established with respect to the amount of lipid solids present in the composition. In the examples, Arbuti The ratio of role sulfate to the total lipid is 1:2. 6 (w/w) there were.

The aqueous solution containing the drug is then mixed with the solution containing the lipid to form a feed solution.

It is important that the feed solution be free-flowing. For this purpose, the aqueous solution must contain phosphate. It is important not to The presence of phosphate buffer salts typically makes the aqueous solution It becomes opaque and forms a precipitate after mixing with a solvent containing a substance. The problem is the p■ of the supplied solution. If so, different buffer salts are used in the formulation of the aqueous solution. solution becomes cloudy In some cases, slightly increasing the temperature of the feed solution can prevent crystallization. Tooru To optimize brightness, the ratio of lipid-containing solvent to aqueous solution can be adjusted. good. The presence of crystals in the feed solution can cause line clogging or block the feed solution. Problems may arise in effective atomization of the liquid. Furthermore, if the feed solution is not free-flowing Drying occurs when one or more components selectively precipitate before the solution reaches the atomizer. The solid becomes non-homogeneous and vines.

The feed solution has a concentration of 3 to 4% total solids in suspension in the final feed solution. Spray drying was successful. Always a good powder when dried at 3.5% solids concentration A final product was produced. Powder viscosity is affected by ambient humidity. Effect of ambient humidity Use compressed air or nitrogen gas as a heated suction gas source to minimize did. In some cases, the quality of the sample powder can be improved by vacuum drying it overnight. Ru. Upon further drying, the powder becomes more free-flowing, allowing further measurements such as % encapsulation. This makes handling easier.

Many commercially available spray drying equipment can be used to spray dry the feed solution. Typically A fog dryer uses atomization of a feed solution into a large chamber and heated compressed air or nitrogen gas. involves the entrainment of an atomized solution in a moving stream of hot gas, such as gas. The feed solution is Usually maintained at a constant temperature. The spray drying temperature vaporizes the liquid in the form of macroscopic droplets. should be sufficient to The remaining particles then fall to the bottom of the chamber where they are recycled. cyclopedia, for example by flowing a stream of hot gas. Even small particles can be collected by falling out of the gas stream.

The hot gas, which has been somewhat cooled at this point, is released into the atmosphere or into a cooler. More recycled. There are many configurations for the atomizer and the direction of the hot gas flow. Main departure The two systems described above have an inlet temperature of 58-72°C and an outlet temperature of 34-72°C. Buchi 190 mini spray dryer at ~42°C (example IL and inlet temperature approx. N1ro 53 spray dryer (Examples 1-3) at 165°C and outlet temperature of approximately 70°C Met.

Example 1.2 includes 25 near 0:5 and 14. 3: 80: 5. 7 (v/v/v) ratio of two water:ethanol: using “Freon 11” system Buchi discloses the characteristics of spray-dried powders. The range of % encapsulation is 6 The water content of the powder was low, about 1-3%. Shown in Table 2 The data also indicate that the powder obtained by this method is generally freshly spray-dried or Show that the wood is fluid either after the second drying, which is carried out under vacuum. of powder Adhesion should also be maintained at low ambient humidity or by collecting the powder and drying it with Dricrite (trade name). ) was reduced by immediate storage. Even if nitrogen is used as the suction gas source, no flow A mobile powder was produced.

The data presented in Table 3 are based on injections using either the Buch i or N1ro equipment. It is shown that very similar powder products with the same encapsulation ratio are obtained even after mist drying.

The results demonstrate that the method of the invention can be easily scaled up for the production of drug/lipid compositions. It also shows the heart.

The % drug encapsulation achieved by the present invention is consistently about 70% or more (see Table 2). and 3). Typically, % encapsulation is achieved by adding water to the powder in a 2:1 weight ratio. be measured. Pharmaceutical encapsulation of the direct spray-dried powder of the present invention Change the amount of water from 100μl (standard conditions) to 2000μl for the powder. Even if I let it, I will decide. The results obtained are shown in Table 4 and are based on the half-log plot of the data. The lot is shown in FIG. The data show that the amount of rehydration and the apparent % encapsulation are inversely proportional. To show an example.

The straight line part of the curve in Figure 2, that is, the amount of rehydration is in the range of 100 to 1000 μm. The regression line was linear in the area. The results are shown in Figure 3. blower) is in this range. It is a straight line (R=1..00). Extrapolating the plot to zero rehydration yields: The theoretical encapsulation of albutyrol sulfate in directly dried powder is approximately 7 It is shown that it is 5%.

The method of the invention is comparable to spray drying preformed liposomes upon rehydration. A powder containing 4% of the liposome-encapsulated drug is produced. Example 2 (Table 5 ) are the encapsulation efficiency when spray-drying preformed liposomes and the direct spraying of the present invention. Data is shown comparing that of a spray-dried drug/lipid composition. The data is Even if the phosphate buffer salt is removed from spray-dried liposomes formed by The result is a powder with substantially the same encapsulation rate as a mist-dried drug/lipid powder. (Table 5). Spray-dried powder of solvent-free preformed liposomes and virtually This means that powders with equivalent encapsulation can be obtained by direct spray drying. is an important advantage over prior art methods. Packaging the drug before spray drying Pre-forming the encapsulating liposomes is eliminated.

The directly spray-dried drug/lipid compositions of the present invention include a variety of lipids, as described above. It is blended. The only requirement for a major lipid in the composition is that it is a membrane-forming lipid. It means that there is. Example 3 includes phosphatidyl coli of the drug/lipid composition. Phosphatidylglycerol/phosphatidylglycerol lipid formulations have been described. This formulation is Effective in producing directly spray-dried powders in repeated large-scale experiments It was proven to be true. In Example 3, as a solvent for dissolving lipids, Only ethanol was used. 'Freon' was not added.

As can be seen from the data presented in Table 7, this drug/lipid composition is well dried; It had approximately the same residual moisture as the formulation containing cholesterol. arbutyrolus The % encapsulation of Rufete was approximately 70%. Static laser unsample light scattering The mass median diameter of the dry particles determined by In the range of 1 to 20 μm The distribution was bimodal with peaks at about 1 and about 7-10 μl. .

The optimal size for respirable particles is less than about 5 μm. Direct spray-dried drugs/fats Most of the particles of fine powder are well within this range. As the powder rehydrates, dry grains The bimodal distribution of the particles is similar to the normal distribution of liposomes with one peak at approximately 1.5 μm. The distribution changes. Accordingly, the compositions of the present invention are useful for inhalation therapy and for respiratory administration of systemic drugs. Fully suitable for use in medicine.

We describe three types of self-contained dosing devices designed for: As defined herein, The term "self-contained" refers to pressurized fluorocarbons. Rorocarbon propellant released or inhaled by the user or produced within the equipment. Powder aero propelled by a pressure difference created by either a created air stream This means that the sol is produced in self-contained equipment. Pressurized fluorochlorocarbon spray Important features of propellant-based dispensing devices are that the powder does not dissolve in the propellant; That is, the powder particles remain intact.

The devices described in Sections 8 and B below both use propellants for aerosolization. Ru. The device described in C uses airflow drawn from the device by the user. There is. All of these devices refer to the same device, which is also incorporated herein by reference. No. 4,895,719 in proprietorship.

A. Propellant Suspension of Drug/Lipid Powder Particles This system consists of a Convenient for dispensing metered amounts of directly spray-dried drug/lipid composition powders. A conventional pressurized propellant atomizer is used. This system suspends powder for long periods in a suitable propellant. Since it is necessary to keep it cloudy, the storage stability of the powder and propellant components of the cloudy liquid must be checked. must be selected. For this reason, the experiments conducted to support the present invention are , the lipid used to produce the powder is preferably partially or fully hydrogenated. It needs to be a converted lipid.

As mentioned above, the key point in propellant selection is whether the drug/lipid powder particles This means that it remains as it was. “Freon 113” meets this requirement. (CC1, FCCIF2) and H"-y t-nl15" (CCIF, (:F, ) Several types of fluorochlorocarbon propellants are particularly suitable for use in the powders of the present invention. suitable for Commonly owned U.S. Pat. No. 4.895.719 describes these propellants. but destroys only a minimal amount of spray-dried pre-formed liposomes. is disclosed.

Select directly spray-dried drug/lipid powders to form powder/propellant suspensions powder to a final concentration of about 10 to 25 times the total propellant. The amount is expressed as %. Additionally, the final concentration of drug/lipid powder in the total propellant can be adjusted to achieve a given A predetermined, metered dose of drug is suspended in a volume of aerosol suspension. Therefore , for example, containing 0.05 mg of drug per 11 g of directly spray-dried powder. If sea urchin powder is blended and the prescribed dose of the drug to be administered is 1 mg, there will be concerns. The suspension is formulated to contain 20 mg of powder per aerosol dose.

The suspension was prepared as described in commonly owned U.S. Pat. No. 4,895,719. packaged in a conventional self-contained injection device. The device is generally equipped with a suitable aerosolization pressure. Contains a replaceable propellant cartridge holding a propellant suspension underneath. Car) IJ The wedge is designed so that when the valve is pushed inward, a predetermined amount of suspension is released under pressure. equipped with a metering valve designed to The cartridge is activated when the valve is activated. It aerosolizes the suspension released from the cartridge and engages the mouth of the nebulizer. In a conventional nebulizer, which acts to direct the aerosol in the direction towards the user's mouth. Supported. Aerosol emitting devices of this type are known.

The aerosol particles that initially form are propellant droplets containing suspended powder. be. When these droplets are sprayed with air, the propellant immediately evaporates and the selected This results in an air stream of powder particles containing a given dose of drug. Powder particles can be applied to e.g. Upon contact with the above water, liposomal drug encapsulation is formed spontaneously.

B. Entrainment of drug/lipid powder in the propellant In this system, a metered dose of drug The directly dried powder containing the agent is prepackaged in a dehydrated state into release packets. Pake The kit uses a propellant atomizer to direct the powder contents of the packet into an air stream of liposome particles. ! ! Squirt into cloudy liquid. Such a system is disclosed in commonly owned U.S. Pat. No. 4.895. 71.8. The packet contains a measured amount of the prescribed drug. Contains dry drug/lipid powder. Once the packet is delivered to the user, both Seal the ends to keep out moisture and keep the powder loosely in the tubing material. Ru. The seal is preferably a conventional thin polymeric barrier, which Capacitate at both ends of the tubing material to form an unobstructed passageway through the tubing material. Can be easily destroyed.

This system also includes a pressurized propellant such as "Freon" and a di-rosolized propellant stream. including a propellant atomizer equipped with a valve for discharging . In A of the previous section, powder grains The powder particles were brought into contact with "Freon", but even in this system the powder particles seemed to remain as they were. Similarly, the downstream end of the valve received the end of the packet. in a nozzle adapted to couple the packet to the device.

In operation, preferably the sealed end of the packet tube material is inserted into the nozzle. the packet to the nozzle by breaking the seal. tube Seals at the unbonded ends of the material may also be used, e.g., in the case of brittle seals, the tubing material A hole is made by pinching the ends of the material. To release the powder inside the packet , simply move the valve in the spray device. The powder in the packet flows through the tube material. It has been found to be entrained in the passing aerosolized propellant stream. then The propellant evaporates rapidly and a suspended air stream of powder is obtained. Powder suspension as described above. The powder is administered by the user inhaling at the same time as the cloudy liquid is released. be exposed. In a commercial embodiment, there are multiple powder packets, one of which is It will be appreciated that the device is supplied as a nebulizer for each dose.

It uses the airflow produced by the user's inhalation to bring it to the haustorium. Known types of One typical system based on a rosolizer is shown at 42 in FIG. This system The drug/lipid powder is packaged as a packet 44 containing a metered dose of drug in the powder. Supplied in water-free packets.

The discharge device 46 within the system includes a curved tube 48 defining an inlet passageway 50. This inlet passageway 50 as shown receives and retains the packet 44; A nozzle 52 of reduced diameter terminates. The other end of the tube limits the convection area 54 The powder coming out of the packet is distributed over the entire cross-section of the downstream end of the tube and can be used by inhalation. Inhaled into the user's respiratory system. Air convection in the downstream region of the tube is channeled into region 54. It is formed by a hanging paddle 56 which rotates freely on a shaft 58 held therein. In the tube A mouth portion 60 is provided at its downstream end.

In operation, the packet is preferably separated from the "inner" end of the packet as described above. Break the tube and place the other end of the packet in the nozzle without sealing it. user is lips Place it around the mouth of the tube and inhale forcefully to quickly draw the air into the tube. It will be done. As can be seen in Figure 1, the air sucked into the pipe is concentrated at the nozzle. The powder is compressed to form a high-velocity air stream that transports the powder from the packet into the convection area. air flow and The entrained powder hits the paddle, causing it to rotate and causing convection within region 54. . Therefore, the powder becomes more average just before it is inhaled into the user's respiratory tract by inhalation. and distributed over a wide cross section. Powder naturally hydrates to form liposomal drug encapsulation be done.

As far as the aforementioned system is concerned, the system consists of a single dose packet with a plurality of single dose packets. It is delivered to the user in the form of an aerosol tube.

Useful in treating diseases of bronchial constriction. These diseases include peripheral vascular disease and shock. It responds to β2-agonists, which are also useful in the treatment of breast cancer, and may delay delivery in cases of preterm birth. Use it like this.

Patent application related to "liposomal bronchodilator method and system" of the same owner, both in the same family (Interpatent No. 366.299 filed June 1381). Early studies have identified three important aspects of liposomal delivery of β2-agonists to the respiratory tract: showed significant advantages. The first is rapid systemic uptake of the drug. Undesirable side effects are observed after drug administration because the amount of drug in the bloodstream is much lower. removed or reduced to a large extent due to especially the initial rapid rise in systemic medications “Drug-spiking and marked heart palpitations, dizziness, and other Phenomena due to side effects of β2-agonists are largely avoided.

The next important advantage is that liposomal dosing of drugs in therapeutic doses can approximately 1 hour or more after drug administration, the drug is more effective than a comparable amount of the drug in its neat form. The result is that the bronchi dilate. This may be due to asthma or other tracheal symptoms. Effective relief of the disease of brachioconstriction does not result with each dose, and fewer doses are needed. Yes, and patients are not exposed to large fluctuations in the amount of β2-agonists in the body. means.

Third, the rate of drug release from the intrapulmonary dosing site may be affected by the lipid composition of the liposomes. Adjusted by Vine.

The release of drugs primarily in liposome-associated form can be achieved either neat or primarily. To solve various problems encountered when drugs are administered in their raw form. drug moderation In addition to their elegant sustained release characteristics, liposomes protect drugs from oxidation, especially Potentially inflammatory drug that is soluble and therefore must be administered in ultra-finely divided form It acts to protect the respiratory system from drugs that can cause it.

The aforementioned advantages of using liposome-encapsulated drugs also apply to spray-dried compositions. match. Example 4 includes spray-dried and bosomal buteral sulfate. vj! @ solution and commercially available microcrystalline suspension of free base albutyrol (trade name Prov The methods used to compare the bronchodilation and cardiovascular effects between It is listed.

Figure 4 shows the comparison between microcrystalline dosing (less than 1 hour) of free base albutyrol sulfate. Compared to spray-dried or posomal albuteral sulfate, albutyrol Evidence shows that sulfates have longer lasting effects of up to at least 2 hours. This is a graphical representation of the data (Table 8). Furthermore, the data in Table 9 This shows that there is no significant difference in the cardiac/pulmonary effects of albutilol regardless of the relationship.

These results demonstrate that dosing of the spray-dried composition is comparable to that of the liposome-encapsulated drug described above. Show that the drug is effective in achieving its benefits.

Various drugs effective against bronchial or pulmonary diseases have similar advantages in the system of the present invention. Can be administered. For example, when administering drugs into the lungs, lipotherapy is used to suppress the progression of emphysema. The α-1-protease inhibitor is administered to the interstitium of the lungs in a packaged form. Riposo protects the tertiary structure of protease inhibitors from oxidation and transports them across the lung cell membrane. It acts to make it easier to send.

The present invention provides direct spray-dried drug/lipid compositions for respiration in the form of metered doses. Provides a convenient self-contained system for dosing the organ. Immediately in the form of the drug itself There are also some drugs that are useful for use (e.g., Table 7, approximately 30% unencapsulated drugs), several times Some drugs are slowly released from liposomes that rehydrate over time.

Another advantage of the system is that the amount of lipids and entrapped drug is essentially constant from dose to dose. This means that the amount of drug administered each time is relatively constant and predictable. That is. The system is also very small, and the aerosolization device described in Section II is not very large. It is convenient to use because only a self-contained device is required.

B. Medication with systemic effects Many drugs whose primary mode of action requires uptake into the bloodstream can also be administered by inhalation. Can be administered. Inhalation methods release the drug rapidly into the bloodstream and allow intramuscular or intravenous injection. It is much more convenient for patients and cannot be administered orally due to drug stability etc. Suitable for medicine. Until now, drug administration by inhalation has been limited to (a) controlling the total drug dose; (b> inability to achieve long-term or controlled drug dosing; (c) ) Cannot be suspended in the propellant solvent as is or is unstable in its as-is form (d) the drug is extremely unpleasant; (d) the drug requires expensive and cumbersome equipment; (e) the drug is irritating to the respiratory tract; was limited by the following factors.

The present invention overcomes many of the problems that have previously limited systemic drug administration by inhalation. Clothes or minimize. The problem of adjusting drug doses is one of the most difficult problems to solve. That's the issue. Even with the drug/lipid compositions of the invention, the level of systemic uptake The amount of aerosolized material that actually reaches the respiratory tract varies with each dose. It will probably change. However, directly spray-dried drug/fat W, composition is designed to facilitate consistent total uptake. Fat itself is a bulking agent; i.e., it functions as a solid particle carrier or filler, so that the drug can be powdered at high concentrations. When trapped within powder particles, much smaller amounts of particulate material may be required for dosing. Not possible. Therefore, only a small amount of drug will be placed in the "non-target" areas of the mouth and throat. cormorant. Second, drug release in granular form from a propellant aerosol improves drug delivery. Due to its convenient uptake, the system of the present invention allows for the dosing of many drugs in this form.

As previously mentioned, directly dried drug/lipid compositions can be administered systemically with controlled release. The rate of uptake of water-soluble drugs depends on the lipid composition of the liposomes. can be controlled to a certain degree.

The system of the present invention dispenses water-soluble drugs from a convenient, relatively inexpensive, self-contained release device. let As previously mentioned, when drugs are administered in powdered form entrapped in lipids, It is more stable and causes less irritation to the respiratory system. Furthermore, the flavor of the drug is essentially confined to the lipids. Vine concealed in the form of an impregnated powder.

Specific indications for systemic drug dosing include those used to relieve symptoms of angina pectoris. There is encapsulation and dosing of nitroglycerin, a coronary vasodilator. drug formulation typically contains about 30% free drug and is readily absorbed by the pulmonary bloodstream. directly to the heart, which is its main site of action, immediately reducing chest pain associated with angina pectoris be done. The remaining liposome-encapsulated drugs that are encapsulated with more than 70% liposomes are , released slowly at a controlled rate by the liposome composition upon rehydration > for a long period of time It dilates the coronary blood vessels over a long period of time, reducing the pain of long-term thoracotomy.

Oxygen is a peptide hormone that induces and increases the strength of uterine muscle contractions during childbirth. Xytocin was formulated and dosed as described for nitroglycerin. Ru. Currently, medication is administered by intravenous injection, but the location and maintenance of the venous cannula It is a method that requires holding the patient, and in some cases it is difficult to restrict the movement and posture of the patient. This is a great method. The aerosol of directly dried lipid-oxidocin powder is Immediately supplied to the systemic blood circulation, similar to intravenous injection without restricting movement. will last. A wide range of other systemic effects, such as those listed in Section 1. Drugs that may be administered may also be advantageously administered by the system of the present invention.

Although preferred embodiments, uses, and methods of carrying out the present invention will be described in detail, Various other uses, formulations, and methods of implementation described in this document are within the contemplation of this invention. It is admitted that it is within the range.

Example 1 Formulation and Properties of Directly Spray-Dried Drug/Lipid Compositions This example The basic formulation and general manufacturing method of the product will be described.

1.1 Formulation of Directly Spray-Dried Drug/Lipid Compositions Described in this Example Spray drying experiments were performed using the following lipid composition: PHEPCIV-40 : Cholesterol: EPG: α-tocopherol 155:40:5:0.1 ( molar ratio). The ratio of albutyrol sulfate to total lipids is approximately 1:2. It was 6 (w/w). Solvent composition for direct drying in this example is a single-phase solvent system water/ethanol/Freon 11 (V/V/V ratios are in the footnotes of Table 2. Are listed). The solution was spray dried with a final concentration of 3.5% total solids in the solution. I set it.

Drugs in water, cholesterol in Freon and remaining lipids in ethanol. It was dissolved in The lipid solutions were combined and the aqueous drug solution was added. This final solution is It was clear and was used as a feed solution for spray drying. The feed solution is stable at room temperature. No precipitate formed for at least 24 hours.

Compressed air is used for atomization of the feed solution and heated suction air to standardize conditions. Ta. The air used for spray drying produces a free-flowing powder even on days with different ambient weather conditions. The humidity should be consistent to reproduce the formation of powder.

Small-scale spray drying of drug/lipid compositions using the B++ rbi 190 mini spray dryer (Switzerland Frawil (P law i 1) C8-9230 Buchi Labora Buchi Laboratoriums Technique ik) 8G), 70 ONI/h ← standard liters/h) gas flow, 1 ~2ml/a+in feed solution input and 58-72°C 734-42°C inlet/ It was carried out using the outlet temperature.

Large-scale spray drying experiments were conducted using N1ro model 53 portable spray dryer (Denma Two-mouth atomizer (Niro Atomizer) from Copenhagen, Denmark It was carried out using Drying at an inlet temperature of about 165°C, an outlet temperature of about 70°C, 244 ~335a+/min<800-1100 ft/1in) and 2 Feed solution input rates of 8-32 ml 110 in. were run.

The powder produced by spray drying contained 680 mg/g of total lipids and albutyrol sulfate. Funi was 1-275 mg/g. Generally, the nominal composition of powder is as follows: (value expressed as ■ of compound per gram of total powder): Rusulphate 2F 41111g: Phosphatidylcholine 500mg/g; Fatidylglycerol 45.4o+Sig=Cholesterol 181mg/g; and and α-tocopherol 0.5mg/ 1, 2 Characteristics of Buchi Spray Dried Compositions Many of the spray dried powders The characteristics were investigated (see Table 2). % encapsulation of spray-dried powders follows the usual procedure It was measured as follows. The powder is rehydrated in twice its weight of water, typically 1 50 mg of bulk powder in 00 μl of deionized water) and left for several hours. suspension Mixed intermittently in a vortex mixer for about 2 hours and rehydrated - day and night. Next, this concern The suspension was diluted with an isotonic buffer, and the liposomes were pelleted by centrifugal force. Kamisumi The liquid was removed. Both the supernatant and pellets were analyzed for drug content. Abste The UV absorption of roll sulfate at 275°C was measured and the extinction coefficient was determined. The drug concentration was calculated using ε-6,314. Then the concentration of drug in the pellet divided by the total amount of drug present (supernatant and pellet) and multiplied by 100. % encapsulation was calculated.

Table 2 Spray-dried albu produced by direct drying on Buchi 190 Terralsulfate/lipid powder characteristic sample, solvent mixture, encapsulation, visual appearance 5 cups Thing 1 (%) %H, Oc d 375-PYY-44A 69 N[] Fluidity N114.24-KF-68 76±2. N mouth Adhesive Single layer dry 424-KF-], 1.8 80±2 N O tackiness Single layer dry 424-KF-32874±1. 1.16±0.06c Adhesiveness Single layer dry 424-KF-388NA 1.71±0.05″ Adhesiveness Fluidity 0.99±0.01d 424-KF-50880±5 2.77±0.03c Adhesion Fluidity 0.5 9±0.06' Average ″77 Standard deviation ±3 a The solvent mixture used was H, O: EtOH: Freon 11; A = 25 near 0:5 (v/v/v), B=14.3/8015-7 (V/V/V).

The powder in all cases was white.

C. No second drying.

d second dry color e Average of samples prepared with solvent mixture B.

NA: Data not available.

No decision was made.

The water content of the powder was determined by Fisher.

Powders have visual appearance (this includes a description of their color and whether they are flowable or not). I also evaluated it.

As can be seen from the data presented in Table 2, the drug/lipid composition (69-80 % drug encapsulation and less than 2.7% water content. Furthermore, the powder is generally white was liquid. If the directly dried powder is sticky, vacuum dry it for another day and night. Dry. After this additional drying, the powder becomes more free-flowing and can be used for other purposes such as encapsulation. The task of measuring has become easier.

1, 3 Spray-dried raw materials produced by Buchi and N1ro spray dryers Comparison of products Spray drying using Buchi 190 and N1ro 53 spray dryers A comparison of the drug/lipid compositions tested is shown in Table 3. The feed solution formulation was as described above. there were. The solvent composition was 14.3.80:5. 7 (V/V/V) ratio Water: Ethanol: "Freon 11".

Table 3 Typical direct dried samples produced on Buchi 190 and N1ro 53 machines. Powder appearance white, fluidity white, fluidity cream color, fluidity ABS 275 276 273 % Encapsulation > 50 69 70 Phospholipid phosphate (mg/g) 20-4 27.1 22.8 PC (%) 91. 7 89.4 N[]”PG (%) 8.3 6.1 N mouth 0LPC (%) 0 1.6 N mouth 0 Depends on PH buffer salt 3.4 3-6 Water content (%> 1.9 5.3 1.0”ND Not determined These comparisons reflect the large number of powders obtained from Buchi and N1'0 that were measured. Showing that they are very similar in terms of properties. - of the observed difference is N1ro This means that the water content in directly dried powders is relatively high. this The differences do not appear to affect other properties.

In the spray drying experiments conducted using the N10 spray dryer, fine powder was produced. were collected in a jar and placed on Drierite (trade name) immediately after collection.

Scanning electron microscopy analysis showed that the diameter of the powder particles was 2-3 μl.

The encapsulation of albutyrol sulfate after rehydration was 70%.

These results indicate that the drug encapsulation rate in the powder produced by direct drying is high. to prove.

1.4 Change in rehydration amount The amount of water per 50 Iog of bulk powder is 100 μm (standard conditions) to 200 μm After changing to 0 μl and rehydration, drug encapsulation was determined. The results obtained are shown in Table 4. and a half-log plot of the data is shown in FIG.

20-17--□7- The data show a dramatic inverse relationship between amount of rehydration and apparent % encapsulation. Powder re-watered This shows that the encapsulation rate decreases by a significant amount as the total amount increases.

In the straight part of the curve in Figure 2, i.e. in the rehydration range from 100 to 1000 μm, It was a linear regression line. The results are shown in Figure 3. The plot is a straight line in this range (R・1.00>. Extrapolating the plot to the amount of rehydration O, The theoretical encapsulation of roll sulfate is found to be 75%.

Example 2 This example shows how a liposomal composition spray-dried with a drug/lipid composition of the invention was prepared. Compare with prior art methods of generating. Lipid composition, pharmacological content, and solvent formulation are It was substantially as described in Example 1.

Weigh the lipid components, dissolve them together in chloroform and dry them onto the walls of a round-bottomed flask. dried (e.g., U.S. Pat. No. 4,766.046 and U.S. Pat. No. 4,483.9) (See No. 29). 10-phosphate buffer composition containing albutyrol sulfate Rehydration buffer was used in place of water as the aqueous solvent. Then add rehydration buffer. The thin film was soaked in water at 45°C for 1 hour with constant mechanical stirring. It made me feel at ease. The obtained liposome dispersion was processed using a high-pressure extruder to obtain 0.2 μm Nucl. Passed through an epore membrane (Nuclepore, California) I did the sizing.

All liposome preparations were purified by ultracentrifugation using isotonic phosphate buffer. The encapsulated drug was removed. Then, the obtained liposome base) (LP-phosphate) was Store under nitrogen atmosphere in glass serum bottles capped with butyl rubber at 2-8°C. Ta.

A second similar composition using water containing albutyrol sulfate as the hydration solution. (LP-water).

2.2 Spray drying of preformed liposomes 2.1 Liposomal base 1-LP - Phosphate and T,,P-water were diluted in isotonic phosphate or water, respectively. Individual When the resulting liposome suspension is combined with the ethanol/Freon solvent system, the The final solid concentration was 3.5%. These feed solutions were then prepared as described in Example 1.1. It was dried in a Shigo N1ro spray dryer as described above.

A drug/lipid composition was prepared as described in Example 1. Spray-dried Posome (LP-phosphate and LP-water) and drug/lipid (D/L-composition) composition All materials were rehydrated as described in Example 1.2 and the results were obtained for each composition. The % encapsulation obtained is shown in Table 5.

Table 5 Sample % encapsulation 0 LP-phosphate 52153 LP-Wed 70/71 D/L-Composition 70/74 (0 double measurement) The results obtained indicate that the ribosol paste was produced without the use of phosphate buffer salts. In cases where the drug/lipid composition of the present invention is equivalent to preformed liposomes, Indicates that the encapsulation rate is given.

Example 3 Phosphatidylcholine/phosphatidylglycerol/arbutyrol sulfate This example shows that the liposomal encapsulation side does not contain cholesterol but upon rehydration. Drug/lipid formulations effective in forming the construct are described. Spray drying method (well, Niro spray drying except that nitrogen is used as the suction air source instead of compressed air The method of using the device was as described in Example 1.

3.1 Composition of drug/lipid supply solution The drug/lipid delivery solution contained the ingredients shown in Table 6.

Table 6 Ingredients Manufacturer lI1g/g feed solution Required number of g albutyol sulfate Agvar Cbemical 12, 3 98. 1PHEPC I V40 Asahi Chemical 20.09 167, 196% egg PG Asabi Chemical 1.112 1L6a-):17E0-L Hoffman-La Roche O,0223 0.17B ethanol, water. LISP Il. s. lndustrial 794.0 6352.0 Water, purified. USP Kendall McGaw 171.0 1368.0 Total: iooo. o Sooo. .

As shown in Table 6, the typical amount for spray drying experiments was 8 kg. feed solution has a total solids (W/v) of 3.5% and the weight ratio of ethanol to water! 14 ．． The ratio was 64:1. This formulation did not contain Freon.

The nominal analyte concentrations in the feed solution were as follows: Albutyrol Sufu 1/F 12, 3 mg/g feed solution and total phosphorous 9 0 4. 5μ pile supply solution.

3,2 Characteristics of spray-dried drug/lipid compositions Table 7 shows the characteristics of spray-dried drug/lipid compositions. / Compiled data collected to characterize lipid compositions.

Table 7 Powder specifications Analysis Present invention IND Confirmation Same retention time as ABS Arbutyol sulfate, -) () IPLC) 34.3 ± 17 mg/g 343±34mg/g total phosphorus 25.3±''2.53 phosphorus/g 25.3±2,53 Confirmation of Aihachi phospholipids Compatible with phosphatidylcholine (cowpIy) Compatible with phosphatidylglyceride Roll Compatible Compatible α-Tocopherol Confirmation Compatible Compatible Residual Moisture (Fish er) NIJT 2%. (20mg/g) 8M7 2. 5% pH. Distilled water 3% 3-5 TB [l residual ethanol (GC/Is) NMT 500P pH NMT 50011pI11% Encapsulation 70±7% 70±JO% Do not exceed that amount of NMT TBD should be determined The concentration of albutyrol sulfate is determined by solubilizing liposomes and Determined using HPLC analysis under conditions that liberate sulfate. freedom The peak corresponding to albutyrol sulfate was Quantified by comparison with butyrol sulfate. albutyrol sul Confirmation of free albutyol sulfate and commercially available albutyrol sulfate Determined by coaigration of base sulfates. Established.

Total phosphate was determined by Bartlett analysis (1959, 8.1rtlett ) was determined. Confirmation of phospholipids and α-tocopherol is performed using thin layer chromatography. Determined by comparison with fees and commercially available standards. The residual water content of the powder is determined by Fish Determined by the method of er. The residual ethanol concentration is determined by gas chromatography. More decided. Microbial limitations require a series of dilutions of the rehydrated drug/lipid composition. coated on a solid agar-rich medium (e.g. LB, Maniatis et al.) and Determined by counting Ronnie forming units (CFU).

Liposome powder granules resulting from direct spray-dried drug/lipid and powder rehydration The mass median diameter of the particles was determined by static laser unsample light scattering (matrix Mulveen I of Southborough, Sachusetts Malveen by Malveen Instruments Mastersizer II) o The mass median diameter of dry particles is 5μI However, the particle size distribution was bimodal with peaks at approximately 1 μm and 7 to 10 μm. there were. Upon rehydration, a normal distribution appears with a single peak at approximately 1.5 μm. .

Example 4 Spray-dried or bosomal albuterol sulfate suspensions for bronchodilation and and cardiovascular effects This example shows a microcrystalline suspension (scaling (Sch ering), Proventil(TM) inhaler) and spray-dried or bottled Bronchodilation and and cardiovascular effects.

4.1 Preparation of metered doses of albutyrol sulfate Albutyrol The metered dose inhaler is manufactured by industrially prepared Scaring Corporation, Kenilworth, Sea Proventil (trade name) inhaler from Schering Corp. Loft $88BS 54). This product contains albutyrol in base form, Designated 90 μg albutyrol free base (108 μg albutyrol sulfate) ) is emitted.

A metered dose of liposomal albutyrol sulfate (MDI-L-ABS) The dose inhaler was prepared in several steps. Albutylo entrapped in liposomes Rusulphate (LP-water) is the actual product except that α-tocopherol is omitted. Produced in the same manner as in Example 2.1. The concentrate was then diluted in aqueous buffer and spray dried. Upon drying, a flowable liposome powder was obtained. Albutyrol sulfate is 273mg/g.

The phospholipid concentration is 709 μIIIo l/g (the total lipid concentration is 1180 umol/g) g). This powder is combined with a propellant and placed in a measured dose vial (3M /jiiker). Albums from the metered dose inhaler valve The emission of tyrol sulfate was determined spectroscopically to be 111 μg per operation. It was decided that

Histamine diphosphate (Sigma Chemical Co., St. Louis, Missouri) (Sigma ChelIIical Co, )) is 50μ+! ,’1 0.11 daily as a solution. 9 in brine and stored on ice until use.

4.2 Test animals and measurement methods A male Hartley (Ha, rt!e), 4-7 weeks old, weighing 350-500 g. y) Species guinea pig (Cavia porcellus) us)) is Harlan 5praque , Inc.). After receiving the items from the seller, we weigh them, Animals were isolated in pairs for at least 3 days and reweighed. Water and Purin a) Guinea food was provided and the animals were allowed to eat ad libitum.

Animals showing weight loss or obvious signs of illness were not used in the study. They are Randomly divided into test groups.

Lung and heart function were measured as follows. Xylazine guinea pigs: Anesthetized with an intramuscular injection of ketamine (2,5:75aH) kg. trachea, esophagus, The left common carotid artery and left jugular vein were exposed and polyethylene tubing material was inserted.

The guinea pigs were then placed supine in a whole body hemograph. Remove the tracheal cannula The patient was connected to a vent and allowed to breathe from room air. Volume changes in the chest cause airflow to the blood volume meter. I set it.

This airflow was measured with a Validyne MP-45 differential transducer, A pressure drop was detected that exceeded the constant resistance element of the hemovolume meter. Airflow signal automatically The integrated and varying capacity was measured. Chest pressure, esophageal cannula and Stat Measurements were made indirectly using a HAM P23Dc fluid-filled transducer. all Physical arterial blood pressure (cardiac diastole) was measured using a Statham P23Db transducer. - was measured from a catheter in the common carotid artery.

All transducers pass through a Validyne carrier detector Coupled to a Model 6 lung mechanics analyzer. The analyzer will respond to equal amounts of variation. The airflow and chest pressure are calculated by computer to calculate the lung resistance (RL). Using. Data is converted from analog to digital form and transferred to Texas Inst. rument Recorded on the Data terminal.

4.3 Metered Dosage of Albutyrol Sulfate For dosing of aerosol inhaler (MDI), a cylindrical dosing chamber (diameter 3. 8 cm, length 13.5 cm, volume 150 cc) for Harvard rodent animals. A respiratory machine and an approximately 10 cm 0.5 cm airway cannula connect to the animal during hemometry. 6 cm (1/4 inch) of Tygon tubing material. MDI Buy Al was activated into the dosing chamber four times. When the drug is administered by adjusting the respiratory machine, the body weight is 1. Respirations were 60 breaths/min with a movement volume of 2 ml per OOg. solenoid valve Activate the ventilator to close the normal (to room air) breathing path and replace it with a ventilator. /Opened the path to the nebulizer. Expose the aerosol in this way for 2 minutes. Ta. Atomized saline was used as a control.

Test animals were placed in a systemic hemograph and basic information regarding lung mechanics and cardiovascular status was assessed. Data was collected. Then, for intravenous injection of histamine (1aHg/kg) The response was determined as follows. 15 minutes after the histamine injection, aerosolized test substance (Proventil™ or MDI- L-albutyrol sulfate) for 2 min with mechanical ventilation as described above. was exposed.

After this dosing (time 0), animals were given an additional dose of histamine for 15 minutes as described above. 1.2.3, and 4 hours later.

4.4 Analysis of results The total lung resistance response (RL) to histamine is the maximum from prehistamine levels. Calculated as change. Before dosing the test substance (-15 minutes), there was no R between groups. To test the hypothesis that there is no significant difference in L, a one-way analysis of variation (Oklahoma Tulta, Statsoft> ANOVA Using.

Significance regarding RL between each time within each group and between each group at each time ANOVA was also used to examine differences. If All0VA shows a difference, then Following the cardiovascular data of the tube (after the first baseline histamine injection) Direct comparison with data collected during the 10 min period (before the second histamine injection) It was evaluated based on the following. Significance of change was determined by ANOVA and post hoc minimum This was investigated using the SD) test.

All graph and table data represent the mean values above and below the standard error of the mean. p< A probability of 0.05 was considered significant.

Regarding Provent i I (trade name) and MDI-L-ABS knee 0 sol A large inhibition was measured for both medications upon injection of histamine at 15 min. However, the 1-hour response for Proventil returned to pre-drug levels. I'm back. For MDI-L-ABS, the inhibitory response was statistically significant up to 2 hours. (See Table 8 and Figure 4).

Table 8 Weighed amounts of Proventi I and liposomal albutyol sulfate 0 Time after aerosol administration of metered dose - 15 minutes + 15 minutes 1 hour 2 Time 3 hours 4 hours Proventil O, 270, 090, 230, 32 0,360-26n=5 ±0.11 ±0.05 ±0.11 ±0.14 ±0.13 Shiga 15 baseline 100 32 86 140 153 1 10% ±6 ±8 ±36 ±42 ±34M0L-ABS O,490, 050,170,360,470,51n=5 ±0.07 ±0.03 ±0 ．． 12 ±0,19 ±0.21 ±0.15 Baseline 100 10 3 5 73 97 105% ±2 ±11 ±19 ±21 ±180 salt water, Proventil (89 μg/actuation of albutyrol free base, or equivalent) 108 μg/acting albutyrol sulfate) and a metered dose of ribosomal albuterol sulfate (92μν-acting albutyrol free salt) or the equivalent of 111 μg/actuation of albutyrol sulfate) Intravenous histamine (1aHg/ kg) of increased pulmonary resistance (RL) response to bronchoconstriction. Values are mean ± SE.

There are also statistics between blood pressure measured after Proventil or MDI-L-ABS dosing. There was a scientifically significant difference (Table 9).

Table 9 Effect of Proventil and liposomal T-lubuterol sulfate on diastolic blood pressure Effect of albutyrol on a metered dose of ate 0 minutes - 1 minute after inhalation of Rosol Heart Visceral diastolic blood pressure (m+nl1g) MOL-ABS n=5 Proventil m =5-1 38.5 33.5 2 20, 8 19.9 ±1.8 ±0.7 3 19, 1 19.0 ±1.2 ±1.1 4 19, 3 19.3 ±1.2 ±1.5 5 18, 8 20.9 ±1.7 ±1.6 6 19, 6 214 ±1.3 ±1.5 7 20, 2 24.8 ±1.2 ±1.3 820, 5 25.7 ±1.2 ±2.3 9 20, 9 257 11.2 ±3.3 1.0 21.5 26.1 ±1,4 ±43 Zero baseline values were obtained at 11 minutes. Proventil (free base Ab sterol.

89μg/actuation, equivalent to 108μg albutyrol sulfate) and lipo Metered dose of arbutitol sulfate (free base Absterol) (92 μg/actuation) aerosol was dosed at 0 minutes.

Although the invention has been described with respect to particular methods and embodiments, the present invention It will be appreciated that various modifications and changes may be made without departing from the above.

Fig, 4 abstract The present invention provides an alternative method to drying preformed liposomes by combining lipids with water-soluble drugs. Discloses a method of directly spray drying a solution of a powder to form a bulk powder. present invention In this method, lipids are dissolved in a solvent and water-soluble drugs are dissolved in an aqueous solution. these The solutions are combined to form a precipitate-free feed solution, which is then powder bed dried. By drying, a bulk powder is produced. This powder, when rehydrated, produces approximately 7 Naturally forms liposomes with high drug encapsulation efficiency of 0%. This direct powder layer drying Powders are particularly useful for drug administration by inhalation.

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Claims (22)

[Claims] 1. (i) an aqueous solution containing a water-soluble drug but not containing a phosphate buffer salt, and a lipid; preparing an ethanol solution; (ii) mixing the aqueous solution and the ethanol solution in a w/w ratio of about 1:1 to 1:5; (iii) forming a solution mixture containing about 3% to 4% (w/v) total solids; spray drying the mixture and recovering the resulting dry particle powder; A method of directly spray drying a drug/lipid powder composition comprising: 2. The water-soluble drug is albuteral sulfate, ephidrine sulfate, Ephidrine Bitartrate, Isoetaline Hydrochloride, Isoetaline Mesylate, Isoproteranol hydrochloride, Isoproteranol sulfate, Metaproteranol sulfate, terbutaline sulfate, procaterol, bitoltello lumesylate, atropine methyl nitrate, cromolyn sodium, propra Narol, fluorosolidide, ibuprofin, gentamicin, tovermicin, Pentamidine, penicillin, theophylline, bleomycin, etoposide, capto Prill, n-acetylcysteine, verapamil, calcitonin, atriopepti alpha-1 antitrypsin, interferon, oxytocin, vasopressin , insulin, interleukin-2, superoxide dismutase, tissue Plasminogen activator, plasma factor 8, epidermal growth factor, tumor necrosis factor, granulocytes/ macrophage colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor a claim selected from the group consisting of a lung surfactant protein, a lung surfactant protein, and a lipocortin. The method described in item 1. 3. The method according to claim 2, wherein the water-soluble drug is albuteral sulfate. . 4. The ethanol solution containing the lipids contains phosphatidylcholine and phosphatidyl group. Ricerol, phosphatidylinositol, phosphatidic acid, phosphatidyl Ethanolamine, phosphatidylserine, sphingomyelin, and choleste at least one selected from the group consisting of rolls, analogues and derivatives thereof; 2. The method of claim 1, comprising a lipid. 5. The ethanol solution containing the lipids contains phosphatidylcholine and phosphatidyl group. Contains lycerol and α-tocopherol in a w/w ratio of approximately 167:15:0.1. The method according to claim 1. 6. Claim 1: The ethanol solution also contains CCl3F and cholesterol. The method described in section. 7. Claim 1 further comprising drying the dry particulate powder under vacuum. How to put it on. 8. 2. The method according to claim 1, wherein the dry mixture is rehydrated by addition of an aqueous solution. Law. 9. Said collection transfers the drug/lipid powder composition into buckets, each containing a predetermined dose of drug. 2. The method of claim 1, further comprising packaging the product in containers. 10. The method of administering water-soluble drugs to the respiratory tract at predetermined doses is A method of producing a pneumatic suspension of a drug/lipid powder composition containing a predetermined dose of drug. wherein the drug/lipid powder composition comprises (i) a water-soluble drug but a phosphate buffered salt; a step of preparing an aqueous solution containing no lipid and an ethanol solution containing lipid; (ii) mixing the aqueous solution and the ethanol solution in a w/w ratio of about 1:1 to 1:5; (iii) forming a solution mixture containing about 3% to 4% (w/w) total solids; Formed by spray drying a mixture and recovering the resulting dry particle powder Method. 11. The drug/lipid powder particles are in a fluorocarbon propellant that does not solubilize the particles. and the production involves storage of the suspension under pressure in a canister, and and to release a selected amount of the suspension in aerosolized form from the canister. 11. The method according to claim 10, comprising: 12. The drug/lipid powder particles each contain a metered dose of drug within the powder. and is supplied to a bucket containing no moisture, and the said production is emptied from the bucket. 11. The method of claim 10, comprising discharging the powder in airborne form. . 13. The manufacturing method uses airflow generated by inhalation of the user to apply the drug/lipid powder to the drug/lipid powder. Accomplished by entraining particles and inhaling them into the user's respiratory tract The method according to claim 12. 14. The production involves applying a pressurized fluorocarbon propellant and an aerosolized stream. A valve for discharging pressurized propellant and means for connecting the valve to a powder bucket. and contacting the aerosolized propellant stream with powder in the bucket. entraining said powder in said propellant stream using an atomization device effective to 13. The method of claim 12, accomplished by: 15. The water-soluble drug is albuteral sulfate, ephidrine sulfate , Ephidrine Bitartrate, Isoetaline Hydrochloride, Isoetaline Mesylate , Isoproteranol Hydrochloride, Isoproteranol Sulfate, Metaprotera norsulfate, terbutaline sulfate, procaterol, vitoltelo mesylate, atropine methyl nitrate, cromolyn sodium, propyl Lanalool, fluorosolidide, ibuprofin, gentamicin, tovelmicin , pentamidine, penicillin, theophylline, bleomycin, etoposide, cap Topryl, n-acetylcysteine, verapamil, calcitonin, atriopep Chin, alpha-1 antitrypsin, interferon, oxytocin, vasopressin insulin, interleukin-2, superoxide dismutase, group Tissue plasminogen activator, plasma factor 8, epidermal growth factor, tumor necrosis factor, granulocytes /macrophage colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor a protein selected from the group consisting of factor, lung surfactant protein, and lipocortin. Scope of Claim 10. The method according to item 10. 16. A device for dispensing a water-soluble drug at a predetermined dose via the respiratory tract, the device comprising (i) ) Aqueous solutions containing water-soluble drugs but without phosphate buffer salts, and ethanol containing lipids. preparing a solution; (ii) mixing the aqueous solution and the ethanol solution in a w/w ratio of about 1:1 to 1:5; (iii) forming a solution mixture containing about 3% to 4% (w/v) total solids; Formed by spray drying a mixture and recovering the resulting dry particle powder a drug/lipid powder composition; and a drug/lipid powder containing the drug at said predetermined dosage. Apparatus for producing a pneumatic suspension. 17. The drug/lipid powder is a fluorocarbon that does not solubilize the drug/lipid powder particles. said powder/propellant suspension suspended in a propellant and said device pressurized; and a canister for delivering a predetermined amount of the suspension in aerosolized form. and a valve connected to the second canister. . 18. Claim 17, wherein the fluorocarbon propellant is CCIF2CF3. Apparatus described in section. 19. The drug/lipid powder particles each contain a metered dose of drug within the powder. and a moisture-free bucket, and the device is supplied to a bucket that does not contain water; 17. The method according to claim 16, further comprising means for discharging the powder in airborne form. Device. 20. The device uses the airflow generated by the user's inhalation to deliver the drug/lipid powder. Claim 19: entrains powder particles and causes them to be inhaled into the respiratory tract of the user Apparatus described in section. 21. The device includes a pressurized fluorocarbon propellant and an aerosolized stream. a valve for discharging said propellant and means for connecting said valve to a powder bucket; and contacting the aerosolized propellant stream with the powder in the bucket. Claims: 1. An atomizing device which is effective for the purpose of Apparatus according to clause 19. 22. The water-soluble drug is albuteral sulfate, ephidrine sulfate , Ephidrine Bitartrate, Isoetaline Hydrochloride, Isoetaline Mesylate , Isoproteranol Hydrochloride, Isoproteranol Sulfate, Metaprotera norsulfate, terbutaline sulfate, procaterol, vitoltelo mesylate, atropine methyl nitrate, cromolyn sodium, propyl Lanalool, fluorosolidide, ibuprofin, gentamicin, tovelmicin , pentamidine, penicillin, theophylline, bleomycin, etoposide, cap Topryl, n-acetylcysteine, verapamil, calcitonin, atriopep Chin, alpha-1 antitrypsin, interferon, oxytocin, vasopressin insulin, interleukin-2, superoxide dismutase, group Tissue plasminogen activator, plasma factor 8, epidermal growth factor, tumor necrosis factor, granulocytes /macrophage colony stimulating factor, granulocyte colony stimulating factor, macrophage colony stimulating factor a protein selected from the group consisting of factor, lung surfactant protein, and lipocortin. Scope of Claim 16. The apparatus according to item 16.