JPH05500229A - Aerosol formulation of solid polypeptide microparticles and its manufacturing method - 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] Aerosol formulation of solid polypeptide microparticles and method for producing the same [Field of the Invention] The present invention relates to a novel aerosol formulation of solid polypeptide microparticles and a method for producing the same. It is something to do.

[Background of the invention] In recent years, many attempts have been made to use bioactive polypeptides as medicines. . Polypeptides used as protein preparations are required to have high medicinal efficacy; It has few side effects and high stability. Regarding formulation, polype Peptide is generally administered as an injection, which means that the polypeptide is fermented in the gastrointestinal tract. This is because the molecules are large and cannot enter the blood circulation. Because it is degraded by enzymes during the process of administration, biomembranes may be damaged in other parts of the body other than injection administration. This is because it is not absorbed very well. Polypeptide administration includes intravenous injection, Intramuscular or subcutaneous injections are usually given, but oral or transdermal administration is not possible. Not known. Under these circumstances, it is important to improve the administration method of polypeptides. It is needed to eliminate the complexity of handling and reduce the physical burden on patients.

Inhalation is a desirable method for polypeptide administration. A solution containing small droplets of aqueous solution. Allosols are made by spraying an aqueous solution with a jet nebulizer. one On the other hand, aerosols containing solid particles can be produced by metered dose nebulizers or dry powder inhalers. It will be done.

Both are used for the treatment of asthma, such as β2-adrenergic antagonists, steroids, It is used in the administration of anti-allergic drugs, etc.

Particle size is key to determining the site of particle deposition in the bronchi. Can reach alveoli Small particles must have a diameter of 0.5 to 7 μm (Pnrnzh et al, J, ^tajt, Pharm, ^■.

Recently, a solid aerosol of insulin has been developed as an aerosol preparation of a polypeptide. (Lee and Sci*rri, J, Phxrs, Sci, 65°567 , 1976) and an example of nebulizer administration of recombinant αl-antitrypsin ( Hobbsrd et if,, Proc, N! 11. Actd, Sc i, U, S, A, 86.680.1989), etc. have been reported. this In these examples, it is said that the appropriate diameter of the aerosol particles is 5 μm or less.

On the other hand, in the case of nasal administration of polypeptides, liquid aerosol, solid aerosol and However, larger particle sizes are required.

For example, a liquid spray of human leukocyte IFH is used to prevent rhinovirus infection. used (ScoN el *1. Br, Med, 1., 284).

1822, 1982), and its polypeptide formulation for intranasal administration was published in Japanese Patent Publication No. 62- 37 (described in No. 116, the effective particle size is determined to avoid deposition of particles in the lungs). It is limited to between 10 μm and 250 μm so that the European Patent No. 2579 No. 56 is a peptide growth factor and tumatropin, somatrem, interleukin. (IL)-1 or -2, interacts with tumor necrosis factor (TNF)-α or -β. Cytokinins such as IL-2 (IFN) or a combination of IFN and IL-2 A device for intrapulmonary administration and its dispersion is described. However, the present invention In the case of IFN alone, IL-6, IL-8, IL-11, antibodies, antibody fragments, etc. For fragments and immune complexes, there are published studies in this literature that promote absorption. To achieve this goal, we are developing an IFN-β formulation for intranasal administration using an enhancer. deer However, even if a penetration enhancer is used, its bioavailability is not recognized as a drug. The price is too low for a product that can be sold.

To efficiently administer polypeptide particles, simply control the particle size. Instead, it is also necessary to formulate formulations with high efficiency. Therefore, each page The best solution for aerosol formulations in both liquid and solid states for putide. Suitable conditions must be determined.

More recently, aerosols of proteins and other macromolecules have been used to produce systemic effects. Administration using sutures has been reported. Recombinant forms of IFN-γ and tumor necrosis factor (De bs et Il, , J. Immunol.

It was observed that the sol migrated into the bloodstream after administration. Recombinant human growth hormone (H GH) is rapidly absorbed from the lungs when administered by liquid aerosol; In animal experiments, it was shown to promote growth in the same way as when administered by subcutaneous injection. It's being made fun of.

In these examples, aerosols containing proteins are generated using a jet nebulizer. It was prepared from an aqueous solution of However, in the case of IFN-β, the protein is Very unstable in aqueous solutions and in jet nebulizer recirculation; Common devices that form losols can lead to molecular aggregation of IFN-β and its physiological effects. It makes the action inactive.

[Summary of the invention] The present invention relates to a novel aerosol formulation of solid polypeptide microparticles. . The formulation of the present invention contains a physiologically active polypeptide with an effective particle size of 0. 5~10μ Contains m solid fine particles. Furthermore, the microparticles of the present invention contain human serum albumin. and/or sugars or sugar alcohols to ensure polypeptide stability. In addition, the preparation of the present invention may contain a surfactant to improve the dispersibility of the fine particles. It can also contain agents. The physiologically active polypeptide of the present invention includes human IFN-α, Antiviral cytokines such as β, γ and immunomodulatory cytokines such as human IL-6, 8. It is a nodal cytokine. The polypeptide targets either the upper or lower airways. It can be prepared as a dry powder by pulverizing it to an appropriate particle size so that it can be used as a target. Pressure type Polypeptide administered by oral inhalation, pressurized by a metered dose device (MDI) Petite aerosol suspensions are desirable for local or systemic use in animal studies. It was found to be effective. Physiological response obtained by polypeptide aerosol The response is superior compared to that obtained by parenteral administration.

[Brief explanation of the diagram] Figure 1 shows that the crushing pressure is high for micronized freeze-dried human serum albumin (HSA) The effect on effective particle size is shown. Figure 2 shows IFN-MDI inhalation in rabbits. Figure 2 shows the deposition of IFN-β in the respiratory tract. Figure 3 shows rabbits after inhalation of IFN-MDI. The serum concentration of IFN-β is shown.

[Detailed description of the invention] Aerosol formulations have the major advantage of being easy to administer drugs. Ru. However, many bioactive polypeptides have specific characteristics. Therefore, a general method for providing stable formulations has not yet been established. parable For example, some polypeptides have their physiological activities due to oxidation, aggregation, and spontaneous activation in aqueous solutions. There are things that are lost through self-digestion. into a solution using a jet nebulizer When spraying polypeptides during spraying, additional shearing force is applied during spraying, resulting in physiological Further loss of activity may occur. Regarding polypeptide aerosol formulations , the solid state is more suitable for maintaining biological activity.

The present invention provides solid polypeptide aerosol formulations for administration to the respiratory tract.

The polypeptide contains antiviral cytokines (human IFN) and immunomodulatory sites. kine (human IL). Here, the cytokines are ■FN-α, β , γ and! They are L-1 to IL-11.

These polypeptides range from naturally occurring to recombinant micropeptides using genetic recombination technology. Organisms (e.g. E. coli, yeast), recombinant insect cells (e.g. silkworms), recombinant mammals cells (e.g. hamster ovary cells, mouse C127 cells, monkey CO8 cells), etc. , and may be chemically synthesized. Polypeptides are extracted in a solution system and It is refined until it meets pharmaceutical standards. For unstable polypeptides, human serum Lubumin (ISA) may be added to the purified polypeptide (0.5% (W/W) below L), some kind of sugar or sugar alcohol may be added if necessary.

[The symbol (w/w) indicates the weight of that component per unit weight of the formulation. ] Sugars or sugar alcohols include lactose, maltose, sorbitant, trehalose , xylose, mannitol, sorbitol and xylitol. is also one. Sugar or sugar alcohol can be added to the polypeptide at a concentration of 0.01 to 200% (W /W), preferably 1 to 50% (W/W). Freeze the mixture. After drying, crush.

The particle size is adjusted by the crushing pressure during the crushing process. Grinding pressure is 5-12 Adjusted to a range of 0 psig, but for large particles (4.0-10 μm in diameter) 5 to 15 psig is preferable for small particles (0.5 to 4.0 μm in diameter). Therefore, 15 to 100 psig is preferable.

This pulverization produces solid fine particles with an effective particle size of 0.5 to 4.0 μm for suture administration. Solids with an effective particle size of 10 μm or less for administration to children, nose and upper respiratory tract Fine particles are generated. The particle size distribution should be 50% or more of all particles, preferably 75% or more. The above is considered to fall within this range. The particle size of the powder in suspension is Centrifugal sedimentation type particle distribution analyzer model CAPA-70 that can measure dispersed powder 0 (Horiba Seisakusho) or QCM-Cascade Invactor PC-2 type (Cil Nornix Messur! by menjInc,,C^,U,S,^,) can be measured.

Polypecide with crushed surfactants to promote dispersion and prevent agglomeration in liquid suspensions. Preferably, it is added to putide powder. As surfactants, monoglycerides, di- Nonionic surfactants such as glycerides, fatty acid esters of sorbitan, polyoxygen Cyethylene acid, polyoxyethylene alcohol, and amphoteric surfactant, phospholipid phosphatidylcholine, natural lecithin, and the like. surfactant is sorbitan triolate (SPAN85), soy lecithin, oleyl alkaline At least one of kohl or hydrogenated castor oil derivatives from 0.05 to 2% (w/ W) is preferably added within the range.

The polypeptide formulation of the present invention also contains calcium ions, magnesium ions, sodium ions, Mineral ions such as thorium ions, potassium ions, and chloride ions can be It can be included to maintain the physical osmotic pressure. In addition, if necessary, alveolar-derived A surfactant may also be added to suppress irritation to mucous membranes.

Polypeptide formulations for inhalation can be prepared by evaporation of a liquid propellant or by a high velocity gas stream. Dispersed by shear forces. Generally, polypeptide particles are packed into an airtight container and Atomized by compressed air, compressed carbon dioxide or fluorocarbon propellants. Flo Examples of carbon-based propellants include chlorofluorocarbons (CFC-11, CF C-12 and CFC-114), /\Idrochlorofluorocarbon (HC FC-123, HCFC-124 and HCFC-141), Hydrofluor carbon (RFC-125 and RFC-134a).

The polypeptide formulations described herein are unstable in aqueous solution, such as IFN-β. Particularly useful for polypeptides.

IFN-β is delivered as a dry powder suspended in a propellant using a pressurized metered-dose aerosol. It can also be formulated to be administered as a sol or administered with a dry powder inhaler. It can also be formulated as a dry powder in star pack capsules.

IFN-β is present in solid form in all of these formulation examples. This protein is , is more stable when prepared as a lyophilized powder than in solution.

These aerosol formulations of the invention contain IFN-β prepared as a dry solid. This solves the problem of instability of the same protein in a jet nebulizer, and Allows FN-β to be administered as an aerosol. Developed for this IFN-β The formulation method described above is also applicable to other IFNs and other polypeptides. Main departure The present invention provides a convenient and non-harmful method for administering therapeutically effective doses of interferon. It provides a means to do so.

Suspended aerosol formulations of the invention are administered with a metered dose nebulizer.

There are commercially available machines that utilize this type of device that can administer peptides for local treatment of lung diseases. Examples of devices include Venlolin inhalers (GIIIO, Inc., Re5ex rch Ttixngle I’ark, NC, U, S, ^,) and Ints l Inhalers (Fiscons, Corp, Bedlord, MA, U, S , ^, ) etc. The dry powder formulation of the invention is administered by a dry powder inhaler. Ru. Commercially available dry powder inhalers include Venjolin Rojxhgler ( GllIO,llIC,, Re5es+ch Trisngle Park, N C, U, S.

^,) and 5pinhsler (Fisons Corp,, Bedfo rd, MA, U, S, ^,), etc.

[Example] The invention is further illustrated by the following non-limiting examples.

Example 1: Preparation of micronized IFN-β Ensure that the aerosol component retains IFN-β activity during the preparation of the dry powder formulation. It turned out that. Human serum albumin (ISA), sodium chloride and sorbitol An IFN-β aqueous solution containing 100% of the total amount of IFN-β was prepared to have the composition shown in Table 1.

Table 1. Prescription acid of IFN-β for freeze-drying Solution A Solution B IFN-β 15μg/111 15μg/ml human serum albumin 1.5 mg/it 15 mg/1fNa Cl G, 6 mg/ml O, 6 mg/ atD-Sorbitol 4.5 a+g/ml Total solids amount 2.1 mg/ml 20.1 mg/ml solution in a freeze dryer (Model No, GT4. Le7 bold Colonge.

GermiB) and then the dry powder was transferred to a jet milling device (S ! Milled at urtevsnt, Boston', MA, U, S, ^).

Measurement of freeze-dried fine particle powder by enzyme immunoassay (EIA) (Yuuuki el gl,, J, lm1unossssY, 10. 5 7゜1989). This EIA is based on IFN-β monomer, which is the physiologically active form of the protein. - specific to

Table 2 shows the ratio of IFN-β activity of the powder sample to that of the neat solution. There is. The values in Table 2 indicate that the IFN activity of the stock solution and sample powder was measured twice, and n= 3) is the ratio standard deviation multiplied by 100. IFN-β powder is 1 Eagle's MEM medium supplemented with 0% fetal calf serum (FCS) was added.

IFN activity was determined by lyophilization and powdering during preparation of microparticle powders, as well as formulation ASB. In the crushing process, it showed 65% or more. These are acceptable as fine powder preparations It is possible.

Table 2. IFN-β active lyophilized powder during preparation of fine particle powder B TFN-β activity IFN-β activity Particle size A 107 ± 17% 65 ± 4 ．． 8% 2.3± 1.7μlB 110±25% 1G2± 3.8% 1. 6±1.2 μl jet mill (Sla+jeysnj) was added to the IFN-containing microparticles. It was used in the preparation of In order to prevent impurities from being mixed into the IFN powder during crushing, the Ultra high performance filter (Millipore Corp.).

Bedford, MA, U,S,A,) was used. jet ・The mill has 50% or more particles with a diameter of 3 μm or less, and 90% particles with a diameter of 5 μm or less. The above procedure was performed to prepare the powder.

Fine particle size of 3 μm or less in diameter is required for efficient deposition in the lungs, while , larger particles are deposited in the pharynx and upper respiratory tract. The deposited particles It is solubilized here and absorbed through the epithelium.

As test samples, H8A powder was micronized under various grinding pressures. Particle size is a minefield Measurement was carried out using a particle distribution analyzer CAPA-7 [1 (type 1).

As shown in Figure 1, the effective particle size of fine powder depends on the crushing pressure of the jet mill. Dependent. In order to obtain fine particles with a diameter of 4 μm or less, the crushing pressure should be 15 to 100 Must be psig.

On the other hand, larger particles require the mill to be subjected to lower grinding pressures (5-15 psig). It can be prepared by operating. These larger particles have an effective particle size of 5~ 15 μm, and when administered nasally by a pressurized metered dose device, the main It is deposited in the nose, pharynx and upper respiratory tract.

Example 3: Compatibility of IFN-β with metered dose nebulizer (MDI) aerosol components A series of samples were prepared to examine the compatibility of aerosol components with IFN-β. . Microparticle powder obtained by pulverizing the freeze-dried powder of Formulation B (Table 2) at a crushing pressure of 1100 psi. 4+gg of powder was weighed into a small vial. Inside this vial, The final concentration of surfactant is 0.1% (w/w) or 1.0% (w/w) Surfactant and propellant (CFC-12) were added as shown.

A highly hydrophilic surfactant was dissolved in a solvent (CFC-11).

The sample was then cooled with dry ice and left at room temperature for 2-7 days before being removed from the vial. The bottle was uncapped to allow the propellant and solvent to evaporate. Remaining non-volatile substances, powder Resuspend the powder and surfactant in Exgle's MEM medium 51 containing 10% FCS. Then, the activity of IFN-β in the sample was measured. The activity of the measured sample was measured using microparticle powder. The activity of the sample was compared with that estimated based on the activity of the sample.

Table 3 provides a description of various surfactants suitable for dispersing powders into suspensions. The analysis results are shown below. Propellant CFC-12 and CFC-11 and surfactant Sorbitan triolate, oleyl alcohol, hydrogenated castor oil derivative and soybean Lecithin was found to have no negative effect on IFN-β activity. these realms At a concentration of 1.0% (W/W), the surfactant was - led to a decrease in β activity. This decrease in activity is due to the stability of the microparticle powder in resuspension. This seems to be the result of the surfactant preventing the dissolution. IFN-β activity was determined by Formulation B. was maintained in the powder sample. Sorbitan triolate is soluble in IFN-β. As a monomer, it can promote solubility.

Table 3. Compatibility mixing ratio of 1FN-β and MDI aerosol component 0.1% 1.0 % Oleic acid 10010 23% 26% Oleyl alcohol 10010 1 01% 73% Sorbitan triolate 10010 92% 29% Aeroso Le AT 10G10 27% 31% Soy lecithin 9G/10 98% 53 % hydrogenated castor oil derivative 9G/10 93% 87% cetylpyridinium chloride 9G/10 25% = (102% without addition of surfactant) - solid state and solution To compare the compatibility of surfactants in conditions, formulation B (Table 2) was Eagle's MEM medium containing C8 and 0.1% (w/w) of each surfactant It was dissolved in

After 48 hours of incubation at room temperature, IFN-β activity was measured by EIA. Established.

The results are shown in Table 4. IFN-β activity in the presence of each surfactant is shown in Table 3 The activity was much lower than that in the solid state. This means that IFN-β is It is more stable to surfactants in the body state than in the solution state. It shows.

Table 4. Compatibility of IFN-β in aqueous solution Oleyl alcohol 40% Sorbitan triolate 57% Soy lecithin 16% Hydrogenated castor oil derivative 26% (No surfactant added 57%) The MDI formulation of IFN-β was mixed with four types of surfactants, namely oleyl alcohol. (OA), sorbitan triolate (SPAN85), soy lecithin (sr, ) and hydrogenated castor oil derivative (HCO) at a concentration of 0.1% (w/w). Manufactured.

MDI samples were prepared by the method of Example 3. The preparation yield is shown in Table 5. Formulation A and Formulation B are shown in Table 1.

Table 5. I FN-MDI preparation stock solution using 4 types of surfactants 100/1 00 100/10G freeze-drying 107/107 74/74 powder crushing 65/7 0 101/75 MDI powder-0^　96/68　7815g-5PAN85　81156　- -3L 68/47 100/75 -HCO84158- All IFN-MDI formulations using four different surfactants have a concentration of 50% or more. The preparation yield was . These yields are acceptable for the preparation of MDI. be. Furthermore, the IFN-β activity in the MDI formulation after preparation is at least 1 It has been stable for over a year.

Example 6: Lung deposition of IFN-β after inhalation of rFN-MD I in rabbits I FN-MD I samples were prepared according to Example 5. There are three rabbits 2. New Sealant White Rabbit weighing 9 to 3.2 kg was used. rabbit for animals Lightly restrain the chamber and use a cylindrical spacer (space volume) to cover the nose and mouth. I put on a mouthpiece with 3001) on it. 0A-I FN-MD Fixed from I Solid IFN-β particles were injected into the spacer. When administering to rabbits, MDI Administer the 20-minute packet (2X 1061 [1/Kg) by breathing for about 15 minutes. gave. After 15 minutes of MDI inhalation, the rabbit was treated with thiobental sodium 50IIg/ The patient was delaminated by injection of Kg, and the entire bronchus and lung were removed. These tissues were treated with 10% FC3. Homogenized in Exgle's MEM medium supplemented with IFN-β in the supernatant. Activity was measured by EIA. As shown in Figure 2, ■FN-β is present in the airways. Deposits were observed at all sites.

The total amount deposited relative to the inhaled dose was 23.0±3.6%.

Example 7: IFN-β activity in serum after inhalation of rabbit I FN-MD I Following the method of Example 6, two rabbits received 2X1061 U/animal of SPAN85- IFN-β was administered by inhalation of IFN-MDI. Blood from the auricular vein after inhalation was collected. IFN-β activity in serum was measured by EIA. xFN−° Figure 3 shows the change in serum concentration of β over time. IFN-β is present in all rabbit blood. Significantly detected in the serum.

Example 8: 2'5'-O in rabbit liver by I FN-MD I inhalation Induction of ligoadenylate synthetase (2'5'-AS) IFN-β was administered 2×1 to 10 rabbits for 5 days according to the procedure of Example 6. Inhalation of SPAN85-IFN-MDI at 0610/Kg/day administered by. On the 6th day, the rabbits were sacrificed and the liver was removed. The liver sample was 1 10ml containing 0% glycerol and 0.1% Non1dej P-4[1 The mixture was homogenized in HEPES buffer (pH 7.5). Induced by IFN The enzyme, 2'5'-AS, was converted to 5jtrkel*1. method (Meth odsE+++yIIo1. , 79.194. (1981) Ta. As shown in Table 6, there was an increase in 2'5'-AS in the liver of inhaled rabbits. clearly observed.

Table 6. Increase in 2'5'-AS in rabbit liver after IFN-MDI inhalation Condition Subject: None Yes Control +2 10 2 Inhalation 10 5 5 p<0. '05*Statistical significance of this chi-square test Example 9: MDI formulation of IL-6 and inhalation into rabbits Semen from human fibroblast culture medium produced IL-6 (10 mg/ml).

ISA (1011g/ml), D-sorbitol (3.0mg/ml) and and NaCl (0,6Il1g/a+I) were mixed in distilled water 5011, and the glass It was freeze-dried in vials (10 ml x 5 bottles). Freeze-dried powder, 5 lur Grinding pressure is 100 psig in a 500 ml container of a te ma an + jet mill. Therefore, it was made into fine particles. The particle size of the fine powder was measured using a Umba particle distribution analyzer model CA. Measured by P^-700.

Among the small particles, 83.5% of them were distributed in a diameter of 1.8±1.3 μm. grain 110ll1 and 0.1 (w/w) sorbitan triolate in 101 gal. Mixed in a vial under nitrogen gas atmosphere. Quantitate into the vial After installing the valve of the spray device, fluorocarbon (CFC-114: CFC -12=4:6) was injected into a vial. IL-6 (100mg), It was administered vaginally to one rabbit (2.5 kg) by inhalation according to the method of Example 6. . 24 hours after administration, rabbit blood was collected from the auricular vein, and the number of platelets was counted by blood cell counting. Measured with a device. The number of platelets clearly increased by 210% compared to the value before administration. reached. These results demonstrate the physiologically active effect of vaginal administration of IL-6 to rabbits. It shows.

Figure　1゜ Grinding 7L IJ (ps+9) Figure　2゜ 0 10 20, 30 IFN Mud 1 (%) Figure　3゜ 8+ hours after MDI inhalation (h) Summary book The present invention provides human interferon or human interferon, which is a physiologically active polypeptide. - Concerning the aerosol formulation of Leukine, the polypeptide has a predetermined effective particle size. It is characterized by being in the form of solid fine particles. Lyophilization of aqueous solutions of polypeptides and suitable for administration to the upper or lower respiratory tract, with an effective particle size of 0.5 to 10 μm. Grind to particle size. Spray the polypeptide aerosol suspension in the pressurized metered-dose device. Intracavitary spraying has shown to have desirable local and systemic effects in animal studies. It turned out that it was. The physiological response to polypeptide aerosols is similar to that of parenteral administration. It was better than that.

international search report III@111-1 “＾＠6klllljp-・lyj〒／、7p　Q1z nnAoc international investigation report JP 9100486 SA　46405

Claims (1)

[Claims] 1. selected from the group consisting of human interferon and human interleukin An aerosol preparation containing solid microparticles of a physiologically active polypeptide, the particles comprising: An aerosol formulation having an effective particle size in the range of about 0.5 to 10 μm. 2. Each solid microparticle is further loaded with human serum albumin, sugar or sugar alcohol. The formulation according to claim 1, characterized in that it comprises: 3. The formulation according to claim 1, further comprising a surfactant. 4. 3. The formulation according to claim 2, further comprising a surfactant. 5. Surfactants include sorbitan triolate, soy lecithin, and oleyl alcohol. hydrogenated castor oil derivatives and mixtures thereof. 4. A formulation according to claim 3, characterized in that: 6. Surfactants include sorbitan triolate, soy lecithin, and oleyl alcohol. hydrogenated castor oil derivatives and mixtures thereof. 5. The formulation according to claim 4, characterized in that: 7. A claim characterized in that the physiologically active polypeptide is human interferon The formulation according to item 1. 8. characterized in that the human interferon is human interferon-β The formulation according to claim 7. 9. A claim characterized in that the physiologically active polypeptide is human interleukin The formulation according to item 1. 10. characterized in that the human interleukin is human interleukin-6 The formulation according to claim 9. 11. The polypeptide is administered through the lungs, and the effective particle size of the particles is approximately 0.5 to The formulation according to claim 1, characterized in that it is in the range of 4.0 μm. 12. The polypeptide is administered through the pharynx and upper respiratory tract, and the particle content is The formulation according to claim 1, characterized in that the effective particle size is about 4.0 to 10 μm. 13. A group consisting of human interferon-β and human interleukin-6? An agent consisting of solid fine particles of 0.5 to 10 μm of a physiologically active polypeptide selected from an allosol formulation, the microparticles of which contain human serum albumin, sugars or sugar alcohols; said aerosol product, further comprising a surfactant. agent. 14. The aqueous solution of bioactive polypeptide is freeze-dried, and the resulting dry powder is 2. The method of claim 1, comprising grinding to fine particles under a grinding pressure of 20 psig. Method for manufacturing an aerosol formulation. 15. Claim 14, characterized in that the crushing pressure is 15-100 psig. How to put it on. 16. The effective particle diameter of the fine particles is in the range of about 0.5 to 10 μm. 15. The method according to claim 14. 17. Before freeze-drying, add human serum albumin and sugar to an aqueous solution of bioactive polypeptide. The method according to claim 14, characterized in that a sugar alcohol is added. 18. 15. The method according to claim 14, wherein a surfactant is added to the fine particles after pulverization. How to put it on. 19. Surfactants include sorbitan triolate, soy lecithin, and oleyl alcohol. and hydrogenated castor oil derivatives. The method according to item 15. 20. Claims characterized in that the physiologically active polypeptide is human interferon. The method according to claim 14. 21. The human interferon is characterized in that it is human interferon-β. 21. The method according to claim 20. 22. Claim characterized in that the physiologically active polypeptide is human interleukin. The method according to claim 14. 23. characterized in that the human interleukin is human interleukin-6 23. The method according to claim 22.