HK1083768B - Sustained-release pharmaceutical composition for lung administration - Google Patents

Description

Sustained-release pharmaceutical composition for transpulmonary administration

Technical Field

The invention relates to a sustained-release pharmaceutical composition capable of being administered through lung, a preparation method and application thereof.

Background

It is known that generally, the drug is absorbed faster through the lung than the digestive tract, and the smaller the molecular weight and the higher the oil-water distribution coefficient, the faster the absorption. In recent years, it has been reported that water-soluble drugs and polymeric drugs are also absorbed relatively well. Therefore, the pulmonary administration of drugs has been attracting attention as a novel route for the administration of drugs expected to exert systemic effects, such as insulin, calcitonin, and other physiologically active peptides.

However, some drugs have high activity even in trace amounts, and if the absorption rate through the lung is too fast, the concentration of the drug in the plasma increases rapidly, and side effects may occur. In addition, although pulmonary administration has an effect of good absorption and quick-acting property, there is also a problem that it is difficult to maintain the therapeutic effect of a drug for a long period of time, and a burden on a patient is increased because some drugs need to be administered multiple times.

As a method for maintaining the medicinal effect of an inhalant, there is a liposome preparation used as a liquid inhalant, as described in U.S. patent No. 5192528. However, liposomes are generally unstable and difficult to store stably at room temperature for a long period of time.

Therefore, there is a need for the development of a sustained-release pharmaceutical composition which can control the absorption rate of a pharmacologically active substance into the lung, maintain the drug effect, and can be stably administered via the lung.

Japanese patent application laid-open No. 4-36233 discloses a sustained-release preparation which is prepared as follows: the sustained-release preparation is obtained by making microspheres from an aqueous solution of a water-soluble polymer containing a physiologically active substance, and encapsulating the microspheres with a polymer having hydrophobicity and in-vivo absorbability, and sodium alginate, gelatin, carrageenan and the like are disclosed as the water-soluble polymer. However, there is no suggestion that the sustained release preparation can be administered pulmonary.

Disclosure of Invention

The purpose of the present invention is to provide a sustained-release pharmaceutical composition for pulmonary administration, which contains a pharmacologically active substance and is capable of controlling the absorption of the pharmacologically active substance into the lung and exerting the pharmacological effect of the pharmacologically active substance over a long period of time when the pharmaceutical composition is administered pulmonary.

The present inventors have conducted extensive studies to solve the problems described above in the "background of the invention", and as a result, have found that the above problems can be solved by blending carrageenan with a pharmacologically active substance that can be administered via the lung, and have further studied to complete the present invention.

Namely, the present invention provides the following technology.

1. A sustained-release pharmaceutical composition for pulmonary administration comprises pharmacologically active substance capable of pulmonary administration and carrageenan.

2. The pharmaceutical composition according to 1, wherein the carrageenan is at least 1 selected from the group consisting of kappa-carrageenan (kappa-carrageenan), iota-carrageenan (iota-carrageenan) and lambda-carrageenan (lambda-carrageenan).

3. The pharmaceutical composition according to 1, wherein the pharmacologically active substance is at least one selected from the group consisting of an anticholinergic agent, a β 2 agonist, a steroid, an antiasthmatic agent, an antiallergic agent, an antiinflammatory agent, an antibacterial agent, an antifungal agent, an anti-influenza virus agent, a peptide agent, an antitumor agent, and a vitamin agent.

4. The pharmaceutical composition according to 1, wherein the content of carrageenan in the pharmaceutical composition is 0.001 to 10⁷About weight percent.

5. The pharmaceutical composition according to 1, wherein the carrageenan having iota carrageenan as a main component is contained in an amount of 0.01 to 10 relative to 1 pharmacologically active substance selected from the group consisting of a β 2 agonist, an antiasthmatic agent and a steroid⁵About weight percent.

6. The pharmaceutical composition according to 1, wherein the composition is a powder having an average particle diameter of about 0.1 to 20 μm.

7. A process for producing a sustained-release pharmaceutical composition for pulmonary administration in the form of powder, characterized in that an aqueous solution or aqueous dispersion containing a pharmacologically active substance capable of pulmonary administration and carrageenan is dried and then pulverized or spray-dried.

8. An inhalant comprising the pharmaceutical composition according to any one of the above 1 to 6.

9. An aerosol formulation comprising the pharmaceutical composition according to any one of 1 to 6, a propellant (propellant), and an aerosol container (aerosol container).

10. The aerosol of the above 9, which contains 0.01 to 10% of a pharmacologically active substance⁴About 10% by weight of carrageenan, and²～10⁷about weight percentThe propellant of (1).

11. The aerosol of 9, further comprising at least 1 substance selected from a solvent and a dispersant.

12. The aerosol of claim 11, which contains 0 to 10% of a pharmacologically active substance⁶About 0 to 10 wt% of a solvent³About weight percent of dispersant.

13. A method for pulmonary administration of a pharmacologically active substance to a patient comprises administering an effective amount of the pharmacologically active substance to the patient together with carrageenan.

14. A method for slowly releasing pharmacologically active substance in lung is to administer an effective amount of pharmaceutical composition containing pharmacologically active substance capable of being administered through lung and carrageenan through lung.

15. Use of carrageenan for the preparation of a sustained release pharmaceutical composition for pulmonary administration of a pharmaceutically active substance.

16. Use of carrageenan for the slow release of a pharmacologically active substance in the lungs by pulmonary administration of an effective amount of a pharmaceutical composition comprising the pharmacologically active substance.

The sustained-release pharmaceutical composition for transpulmonary administration (hereinafter also referred to as "pharmaceutical composition") of the present invention will be described in detail.

The pharmaceutical composition of the present invention comprises a pharmacologically active substance capable of pulmonary administration (hereinafter also referred to as "pharmacologically active substance") and carrageenan, and is characterized in that carrageenan is used as a means for controlling the absorbability of the pharmacologically active substance capable of pulmonary administration in the pulmonary administration.

The pharmacologically active substance that can be administered via the lung used in the present invention is not particularly limited to pharmacologically active substances that exhibit pharmacological effects by pulmonary administration to mammals and the like, and known substances that act locally or systemically on the trachea, bronchi, lungs and the like can be widely used. Examples of the pharmacologically active substance include drugs for the central nervous system, drugs for the peripheral nervous system, drugs for the circulatory organs, drugs for the digestive organs, antibiotics, and chemotherapeutics.

Specifically, examples thereof include anticholinergic agents (e.g., ipratropium bromide, fluorotropium bromide, scopolamine bromoacetate, tiotropium bromide), β 2 agonists (e.g., procaterol, phenopropranol, albuterol, formoterol, salmeterol), steroids (e.g., beclomethasone, fluticasone, budesonide), antiasthmatic agents (e.g., theophylline, aminophylline, ozagrel, etc.), antiallergic agents (e.g., ketotifen, terfenadine, azelastidine, epinastine, etc.), anti-inflammatory agents (e.g., diclofenac sodium, ibuprofen, indomethacin, etc.), antibacterial agents (e.g., cefixime, cefdinir, ofloxacin, tostin, etc.), antifungal agents (e.g., fluconazole, itraconazole, etc.), anti-influenza virus agents (e.g., nanowivir, oseltamivir, amantadine, etc.), drugs (e.g., insulin, calcitonin, and the like), antitumor agents (e.g., fluorouracil, gefitinib (gefitinib), vitamin agents (e.g., calcitriol, mecobalamin, and the like), and the like, or derivatives thereof, 1 substance selected from the above pharmacologically active substances may be used alone, or a mixture of 2 or more substances may be used.

The carrageenan used in the present invention is a polymer having a molecular weight of 100,000 to 500,000 obtained by extracting with water plants of Gigartina (Gigartinacea Gigartina) belonging to the family Gigartinaceae, Chondrus (Chondrus) and Eucheuma (Solieriaceae Eucheuma) belonging to the family Solieriaceae, and is a polysaccharide substance containing galactose and 3, 6-anhydrogalactose as main components. The above carrageenans have a sulfate half ester group in the unit structure as shown below, and are classified into 5 types of kappa (. kappa) -carrageenan, iota (. iota) -carrageenan, lambda (. lamda) -carrageenan, mu (. mu) -carrageenan, and eta (. eta) -carrageenan according to the content of the sulfate half ester group.

In the present invention, the 5 kinds of carrageenans can be used alone or in combination. The mixing ratio may be appropriately selected depending on the purpose of use. Of the 5 types of carrageenan, kappa carrageenan, iota carrageenan and lambda carrageenan are preferable, iota carrageenan is more preferable as a main component, and iota carrageenan is particularly preferably used.

The pharmaceutical composition of the present invention contains the above pharmacologically active substance and carrageenan. When the pharmaceutical composition of the present invention is administered to the lung, the pharmacologically active substance is retained in the lung by the action of carrageenan and is slowly released continuously. Therefore, the pulmonary absorption rate of the pharmacologically active substance is controlled, and the concentration of the pharmacologically active substance in the blood plasma is continuously and stably maintained. In addition, the pharmaceutical composition of the present invention also has good storage stability.

The pharmaceutical composition of the present invention may contain the following additives, as required, in addition to the pharmacologically active substance and carrageenan. The additive is not particularly limited as long as it can be used in pharmaceutical preparations, and for example, solid excipients such as white sugar, lactose, glucose, fructose, sucrose, mannitol, sorbitol, arabinose, xylitol, and dextrose; liquid excipients such as inert liquids such as propylene glycol; binders such as methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, white sugar, and the like; lubricants such as magnesium stearate, light anhydrous silicic acid, talc, sodium lauryl sulfate, and the like; preservatives such as sodium benzoate, sodium hydrogen sulfite, methyl hydroxybenzoate and propyl hydroxybenzoate; stabilizers such as citric acid and sodium citrate; suspending aids such as methylcellulose, polyvinylpyrrolidone, lecithin, sorbitan trioleate, oleyl alcohol, polyoxyethylene sorbitan fatty acid ester and the like, or dispersing agents such as surfactants and the like; solvents such as water, ethanol, 1-propanol, and 2-propanol; sodium chloride and the like; pH adjusters such as sulfuric acid and hydrochloric acid.

The kind and amount of the above additives can be suitably selected and used according to the purpose.

The composition and the blending ratio of the pharmaceutical composition of the present invention may be appropriately selected depending on the target disease, the age or sex of the target patient, the condition of the patient, and the like.

For example, in the pharmaceutical composition of the present invention, the amount of carrageenan is 0.001 to 10% relative to the amount of the pharmacologically active substance⁷About (preferably 0.01 to 10 wt.%) in the presence of a catalyst⁶About weight%, more preferably 0.1 to 10⁵About weight percent, particularly preferably 1 to 10⁴About wt.%). In the pharmaceutical composition of the present invention, the amount of the additive to the pharmacologically active substance is preferably 0 to 10⁷About (preferably 0.5 to 10 wt.%) of⁶About weight percent, more preferably 1 to 10⁴About 10 to 10 wt%, particularly preferably³About wt.%).

In addition, as a preferred embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition contains 0.01 to 10% of a pharmacologically active substance (particularly, a β 2 agonist, an antiasthmatic agent, a steroid, etc.)⁵About (preferably 0.1 to 10 wt.%) of⁴About wt.%) carrageenan (especially carrageenan containing iota-carrageenan as main component), and 0-10 wt.%⁷About (preferably 10 to 10 wt.%) of⁶About wt.%) of additives (particularly water, ethanol, etc.).

A more preferred embodiment of the pharmaceutical composition of the present invention includes a composition containing 0.1 to 10% of a pharmacologically active substance (particularly theophylline, procaterol and the like)⁴About (preferably 1 to 10 wt.%) of³About% by weightRight) iota carrageenan, containing 1-10⁶About (preferably 10 to 10 wt.%) of⁵About wt.%) of additives (particularly water, ethanol, etc.).

As a preferred embodiment of the pharmaceutical composition of the present invention, a composition containing 0.1 to 10% of a pharmacologically active substance (particularly, a. beta.2 agonist, an antiasthmatic agent, a steroid, etc.) is mentioned⁴About (preferably 1 to 10 wt.%) of³About wt.%) of carrageenan (particularly carrageenan having iota carrageenan as the main component).

A more preferred embodiment of the pharmaceutical composition of the present invention includes a composition containing 0.1 to 10% of a pharmacologically active substance (particularly theophylline, procaterol and the like)³About (preferably 1 to 10 wt.%) of²About wt.%) of iota carrageenan.

The pharmaceutical composition of the present invention can be used in a known inhalation form (for example, a powder inhaler, an inhalation suspension, an inhalation solution, a capsule inhaler, etc.) and the pharmaceutical composition of the present invention can be prepared by filling an appropriate inhaler (for example, a metered dose inhaler, a dry powder inhaler, a nebulizer, an atomizer, etc.) with the pharmaceutical composition of the present invention at the time of use.

When the pharmaceutical composition of the present invention is used in the form of a powder, the average particle size of the powder is not particularly limited, but is preferably about 0.1 to 20 μm, and more preferably about 1 to 5 μm, from the viewpoint of retention of particles in the lung. The particle size distribution of the powder of the pharmaceutical composition of the present invention is not particularly limited, and the amount of particles having a particle size of 25 μm or more is preferably about 5% or less, more preferably about 1% or less.

The powder of the pharmaceutical composition of the present invention can be prepared by, for example, dry pulverization, spray drying, etc.

According to the dry pulverization method, a powdery pharmaceutical composition can be prepared, for example, as follows: drying raw materials containing an aqueous solution (or aqueous dispersion) of a pharmacologically active substance and carrageenan, and making the obtained dried product into fine particles to obtain a powdery pharmaceutical composition. Specifically, carrageenan is dissolved (or dispersed) in an aqueous medium, a pharmacologically active substance is added thereto, and the mixture is stirred using a homogenizer or the like to be dissolved (or dispersed) to obtain an aqueous solution (or aqueous dispersion). The aqueous medium may be water alone or a mixture of water and a lower alcohol. Examples of the lower alcohol include water-miscible alcohols such as methanol, ethanol, 1-propanol, and 2-propanol. Ethanol is preferred. The obtained aqueous solution (or aqueous dispersion) is dried by air-drying, freeze-drying or the like, and then pulverized or micronized by using a jet mill, a ball mill or the like to obtain a pulverized product having the above average particle diameter. In any of the above steps, the additives may be added as necessary.

In addition, according to the spray drying method, the powder of the pharmaceutical composition can be prepared, for example, as follows: a raw material comprising an aqueous solution (or aqueous dispersion) of a pharmacologically active substance and carrageenan is spray-dried and then micronized to obtain a powder of a pharmaceutical composition. The aqueous solution (or aqueous dispersion) may be produced by the above-described dry pulverization method. The spray drying can be carried out by a known method to obtain a spherical particle-shaped pharmaceutical composition powder having the above average particle diameter.

The suspension for inhalation, solution for inhalation, capsule-shaped inhalant and the like can be prepared by known preparation methods using pharmaceutical composition powder obtained by dry grinding, spray drying and the like, or using pharmacologically active substance and carrageenan which can be administered via lung.

The inhalant composed of the pharmaceutical composition of the present invention is preferably used in the form of an aerosol (aerosol). The aerosol can be formed, for example, by filling the pharmaceutical composition of the present invention and the propellant in an aerosol container. Further, a dispersant, a solvent, or the like may be added as necessary. The aerosol may be any of a two-phase system, a three-phase system, and a membrane system (double container). The aerosol may be in the form of powder, suspension, solution, or the like.

As the propellant, a liquefied gas propellant, a compressed gas, or the like can be used. As the liquefied gas injection agent, for example, fluorinated hydrocarbons (e.g., chlorofluorocarbon substitutes such as HCFC-22, HCFC-123, HFC-134a and HFC-227), liquefied petroleum, dimethyl ether and the like can be used. As the compressed gas, for example, a soluble gas (for example, carbon dioxide, nitrous oxide, or the like), an insoluble gas (for example, nitrogen, or the like), or the like can be used.

The dispersant and the solvent may be used by appropriately selecting the additives listed above.

A known method including 2 steps of a content preparation step and a filling step of filling the content and the propellant into an aerosol container can be used for producing the aerosol.

As one of preferred embodiments of the aerosol of the present invention, the following can be mentioned.

The pharmacologically active substance includes procaterol, theophylline, a steroid, or a salt (hydrochloride, sulfate, etc.) thereof, and theophylline or procaterol (or hydrochloride thereof) is particularly preferable, a substance containing iota-carrageenan as a main component is preferable, a fluorinated hydrocarbon as a substitute for a chlorofluorocarbon, such as HFC-134a or HFC-227 is particularly preferable, and water, ethanol, 2-propanol, etc. are particularly preferable as the solvent, and the weight ratio of water to ethanol is preferably about 0: 1 to 10: 1.

The amount of each component contained in the aerosol of the present invention may be in the following range: carrageenan is 0.01-10% relative to pharmacologically active substance⁴About (preferably 0.1 to 10 wt.%) of³About weight percent), the spraying agent is 10²～10⁷About (preferably 10%) by weight³～10⁶About weight percent), and the solvent is 0-10⁶About (preferably 10 to 10 wt.%) of⁵About wt.%), dispersant 0-10³About (preferably 0.01 to 10 wt.%) of²About wt%).

The pharmaceutical composition of the present invention is safe and effective for pulmonary diseases and systemic diseases in mammals (e.g., humans, mice, rats, cats, dogs, sheep, horses, cows, monkeys, etc.), and can maintain therapeutic effects for a long period of time. For example, they are useful as antiasthmatic agents, antiallergic agents, eosinophil chemotaxis inhibitors, preventive and therapeutic agents for diseases associated with eosinophil infiltration (for example, allergic diseases such as urticaria, atopic dermatitis, allergic rhinitis, and allergic pneumonia), skin diseases such as eczema, dermatitis herpetiformis, and psoriasis, respiratory diseases such as eosinophilic pneumonia (PIE syndrome), and Chronic Obstructive Pulmonary Disease (COPD), and infectious diseases caused by various infectious bacteria. In particular, it is useful as an antiasthmatic agent, a preventive/therapeutic agent for Chronic Obstructive Pulmonary Disease (COPD), a preventive/therapeutic agent for allergic pneumonia, a preventive/therapeutic agent for eosinophilic pneumonia, a preventive/therapeutic agent for infection such as influenza, and the like.

The dosage of the pharmaceutical composition of the present invention varies depending on the kind of pharmacologically active substance, the target disease, age, body weight, symptom, administration route, administration frequency, etc., but an effective amount can be administered in order to exhibit the drug effect of the pharmacologically active substance used, and for example, when the particle diameter is about 0.1 to 20 μm, the pharmaceutical composition is administered to an adult usually 1 to 4 times per 1 day, and the dosage is about 0.001 to 100mg/1 time in terms of the active ingredient (pharmacologically active substance).

The form (e.g., powder, suspension, solution, etc.) of the pharmaceutical composition of the present invention may be appropriately selected depending on the kind of the pharmacologically active substance, the target disease, and the like.

The route of administration is generally preferably by direct inhalation from the oral cavity or the like using an inhalation device.

The pharmaceutical composition of the present invention can be administered directly to the trachea and therefore can rapidly exert the effect of the pharmacologically active substance incorporated therein. In addition, since carrageenan is added to the pharmaceutical composition of the present invention, the pharmacologically active substance can be slowly released into the lung, and the pharmacological effect of the pharmacologically active substance can be continuously exhibited for a long period of time. Therefore, when the pharmaceutical composition of the present invention is administered via the lung, it is not necessary to administer the pharmaceutical composition a plurality of times, and the burden on the patient can be reduced. Moreover, the necessary minimum amount of drug can be administered, thus significantly reducing the side effects caused by the large amount of drug administered. Thus, the pharmaceutical composition of the present invention can increase the therapeutic effect of the drug and reduce side effects.

Drawings

Fig. 1 is a graph showing changes in serum theophylline concentration (n ═ 4, average ± s.d.) when the administration solution a used in test example 1 was administered intratracheally and intravenously.

Fig. 2 is a graph showing changes in serum theophylline concentration (n ═ 4, average ± s.d.) when the administration solutions a to D used in test example 1 were administered intratracheally.

Detailed Description

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

Example 1

(1) Procaterol hydrochloride (particle size 1.8 μm)15mg, (2) iota-carrageenan (product No. C-1138, trade name: Sigma Aldrich Japan Co., Ltd., manufacturer: SIGMA CHEMICAL CO.) (100 mg), (3) HFC-134a (product No. D10252125, trade and manufacturer: Du Pont-Mitsui fluorochemicals Co., Ltd., (4) ethanol (99.5%) 2.0g, and (5) water (10.0 g) were mixed as described below to give a suspension for inhalation.

First, carrageenan was dissolved in water heated to about 80 ℃ and cooled to about 40 ℃, and procaterol hydrochloride was added and stirred using a homogenizer. After 20g of HFC-134a was added thereto under cooling at about-30 ℃ and stirred, ethanol was further added thereto and stirred, and then HFC-134a was added so that the total amount became about 100g and stirred.

The aerosol container was filled with 9g of the suspension concentrate for inhalation, and a metering valve for 50. mu.l of the suspension was attached to the container for inhalation 1 time.

Example 2

Iota carrageenan (product No. C-1138, trade name: Sigma Aldrich Japan Co., Ltd., manufacturer: SIGMA CHEMICAL CO.) (1.0 g) was dissolved in 100g of water heated to about 80 ℃, and after cooling to about 40 ℃, 20g of theophylline was added and stirred using a homogenizer to dissolve it. After drying it with an air blow dryer (SPHH-200, Tabai Espec Corp.), the dried product was pulverized to about 2 μm with a spiral jet mill (50AS, Hosokawa Micron Corp.). Lactose was added to the pulverized material in an amount of 10 times the weight of the pulverized material, and the mixture was mixed by a roll mixer to obtain a powder inhalant.

Test example 1

The following 4 kinds of administration solutions were prepared using theophylline as a pharmacologically active compound. Here, dosing solution B was prepared as the composition of the present invention, and dosing solutions A, C and D were prepared as the comparative compositions.

Administration solution a: theophylline was dissolved in a physiological buffer salt solution (PBS (-), product No.05913, manufactured and sold by Nikkiso pharmaceutical Co., Ltd.) to prepare a theophylline solution of 1 mg/ml.

Administration solution B: iota-carrageenan (product No. C-1138, trade name: SigmaAldrich Japan Co., Ltd., manufacturer: SIGMA CHEMICAL CO.) -was dissolved in the administration solution A heated to about 80 ℃ and then cooled to room temperature to prepare an administration solution B containing 1 w/v% (-10 mg/ml) of iota-carrageenan.

Administration solution C: gelatin (product No.16631-92, product of NaclaiTesque, Inc.) was dissolved in the administration solution A heated to about 80 ℃ and then cooled to room temperature to prepare an administration solution C containing 5 w/v% gelatin.

Dosing solution D: a drug delivery solution D containing 2 w/v% sodium alginate was prepared by dissolving 500 to 600cP (product No.199-09961, manufactured by Wako pure chemical industries, Ltd.) of sodium alginate in the drug delivery solution A.

Male rats of the Wistar line (body weight: about 220g) fasted for about 18 hours were used as experimental animals. Intratracheal administration of drug solutions was carried out according to the method described in Schanker, l.s.et al.am.j.physiol., 222(1972) p 409. That is, the rat was fixed to the back of the body under pentobarbital anesthesia (about 32mg/kg), and the neck was cut along the median line to expose the trachea. A2.5 cm polyethylene tube (i.d.1.5mm, o.d.2.3mm) was inserted between the fourth and fifth tracheal cartilage rings below the thyroid cartilage to a depth of 0.6 cm. 100 μ l of the administration solutions A to D were aspirated into a glass microinjector, a rat was fixed on an animal table at an angle of 80 degrees, the tip of the injector was inserted 1 to 2mm above the trachea branch part through the polyethylene tube, and the intratracheal administration was carried out for 1 to 2 seconds. After about 45 seconds of administration, the animal table was set at an angle of 10 °, and the incision was sutured.

After the above-described operation, the administration solution A was administered intravenously, and 100. mu.l of the administration solution A was administered through the femoral vein.

Blood was collected from the subclavian vein at 0.2ml at 15, 30 seconds, 1, 2, 5, 10, 15, 30 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours after intratracheal and intravenous administration, centrifuged at 1800g for 10 minutes, and the theophylline concentration in the resulting serum was measured by HPLC.

Fig. 1 shows the change in serum theophylline concentration when the administration solution a was administered intratracheally and intravenously (n ═ 4, mean ± s.d.).

Fig. 2 shows the change in serum theophylline concentration when the administration solutions a to D were administered intratracheally (n ═ 4, mean ± s.d.).

Table 1 shows the mean pharmacokinetic parameters (n-4) when the administration solutions a to D were administered in gas-line at an amount of 100 μ g/body. The parameters in table 1 have the following meanings.

AUC_6hr: area under the serum concentration-time curve (μ g hr/ml) up to 6 hours after administration

AUC_inf: area under the serum concentration-time curve (μ g hr/ml) up to infinite hours after administration

C_max: maximum blood concentration (μ g/ml)

T_max: time to maximum blood concentration (hr)

MRT_inf: mean residence time (hr) until infinite hours after administration

MAT_inf: average absorption time (hr) to infinite hours after administration

As can be seen from fig. 1, the pulmonary absorption of theophylline was as rapid and complete as that of intravenous administration.

As is clear from FIG. 2 and Table 1, the change in the theophylline concentration in serum after intratracheal administration of the administration solution B containing 1 w/v% iota carrageenan was compared with the area under the concentration-time curve in serum (AUC) of the administration solution A containing no carrageenan (control)_6hr、AUC_inf) Without reduction, the highest blood concentration (C)_max) Control at 40.2%, time to reach maximum blood concentration (T)_max) 5.5 times higher, Mean Retention Time (MRT)_inf) 2.2 times higher, average absorption time (MAT)_inf) The increase is 4.9 times, and the slow-release absorption dynamic is shown. Therefore, by adding 1 w/v% iota carrageenan, a useful sustained release profile can be obtained from AUC_6hrAnd AUC_infMaintenance of the therapeutic effect represented by (1), represented by (C)_maxReduced side effects represented by inhibition of (2), MRT_infAnd MAT_infThe effective blood concentration maintenance time represented by an increase in (b) is increased.

The administration solution C containing 5 w/v% gelatin, which was confirmed to have a sustained-release effect by 5(6) -Carboxyfluorescein (CF) (molecular weight: 376), suppressed C compared to the administration solution A_maxHowever, T is not observed_max、MRT_infAnd MAT_infNo sustained release effect was confirmed.

The dosing solution D containing 2 w/v% sodium alginate had approximately the same viscosity as the dosing solution B containing 1 w/v% iota carrageenan, but the AUC_6hrAnd AUC_infReduction of MRT_infAnd MAT_infAnd also decreases. It is speculated that the transpulmonary sustained release effect of carrageenan is independent of viscosity, but rather a property specific to carrageenan.

TABLE 1

Drug delivery solution	Dose(μg/body)	AUC(μg·hr/ml)	AUC(μg·hr/ml)	C(μg/ml)	T(hr)	MRT(hr)	MAT(hr)
								A (control) B (Carrageenan) C (gelatin) D (sodium alginate)	100100100100	2.893.963.002.11	4.028.334.012.44	3.961.592.920.96	0.00420.0230.00420.033	4.439.554.293.00	1.326.441.18-0.11

By using carrageenan together with a pharmacologically active substance in the pharmaceutical composition of the present invention, the pulmonary absorbability of the pharmacologically active substance can be favorably controlled, and the drug effect can be exhibited over a long period of time.

In addition, known documents described in the present specification are used as references.

Claims (13)

1. A sustained-release pharmaceutical composition for pulmonary administration comprises pharmacologically active substance capable of pulmonary administration and carrageenan.

2. The pharmaceutical composition of claim 1, wherein the carrageenan is at least 1 selected from the group consisting of kappa carrageenan, iota carrageenan and lambda carrageenan.

3. The pharmaceutical composition according to claim 1, wherein the pharmacologically active substance is at least one selected from the group consisting of anticholinergic agents, β 2 agonists, steroids, antiasthmatic agents, antiallergic agents, anti-inflammatory agents, antibacterial agents, antifungal agents, anti-influenza virus agents, peptide agents, antitumor agents, and vitamin agents.

4. The pharmaceutical composition according to claim 1, wherein the content of carrageenan in the pharmacologically active substance is 0.001 to 10⁷And (3) weight percent.

5. The pharmaceutical composition according to claim 1, wherein the carrageenan-based material contains iota carrageenan in an amount of 0.01 to 10 relative to 1 pharmacologically active substance selected from the group consisting of a β 2 agonist, an antiasthmatic agent and a steroid⁵And (3) weight percent.

6. A pharmaceutical composition according to claim 1, wherein the composition is a powder having an average particle size of 0.1 to 20 μm.

7. A process for producing a sustained-release pharmaceutical composition for pulmonary administration in the form of powder, characterized in that an aqueous solution or aqueous dispersion containing a pharmacologically active substance capable of pulmonary administration and carrageenan is dried and then pulverized or spray-dried.

8. An inhalant comprising the pharmaceutical composition according to any one of claims 1 to 6.

9. An aerosol comprising the pharmaceutical composition according to any one of claims 1 to 6, a propellant and an aerosol container.

10. The aerosol formulation according to claim 9, which contains 0.01 to 10% of the pharmacologically active substance⁴Carrageenan in an amount of 10% by weight²～10⁷(ii) a propellant in weight%.

11. The aerosol formulation of claim 9, further comprising at least 1 substance selected from a solvent and a dispersant.

12. The aerosol formulation of claim 11, which contains 0 to 10% of the pharmacologically active substance⁶0 to 10% by weight of a solvent³(iii) a dispersant in weight%.

13. Use of carrageenan for the preparation of a sustained release pharmaceutical composition for pulmonary administration of a pharmaceutically active substance.