JPWO1993025193A1 - Preparations in containers for intratracheal administration - Google Patents

Abstract

(57) [Abstract] This publication contains application data prior to electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] Preparation for Intratracheal Administration Technical Field The present invention relates to a novel preparation for intratracheal administration. More specifically, the present invention relates to a preparation for intratracheal administration in which a powder formulation for intratracheal administration is contained in a container comprising at least one component selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch, hydroxypropyl starch, and sodium alginate. More specifically, the present invention relates to a preparation for intratracheal administration in which a powder formulation for intratracheal administration is contained in a container comprising at least one component selected from the group consisting of cellulose derivatives and analogs, i.e., hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch, hydroxypropyl starch, and sodium alginate, and the drug in the powder formulation for intratracheal administration is less likely to adhere to the container, thereby improving the amount of drug delivered from the container to the airways.

BACKGROUND ART The airways, which extend from the nasal cavity and oral cavity to the pharynx, larynx, trachea, bronchi, bronchioles, and alveoli, are the passageways through which air is exhaled and inhaled during breathing.

Many diseases, such as nasal allergies, asthma, bronchitis, and emphysema, occur in the respiratory tract. The drug administration methods for treating these diseases can be divided into two categories: systemic administration, such as oral administration or injection, and local administration to the respiratory tract, such as aerosols or inhalants.

Oral administration is easy and injections are reliably absorbed, making these systemic routes of administration widely used. However, local administration within the airways is valuable in terms of the drug's ability to concentrate at the site of action, reducing side effects, and providing a rapid onset of action.

In addition to local administration for diseases occurring within the airways, as described above, there have been recent attempts to transfer drugs from the alveoli to the bloodstream by taking advantage of the small barrier between the alveoli and the blood vessels. Airway administration has also attracted attention as a method for systemic administration of peptides and proteins, which are metabolized and inactivated in the intestinal tract or liver when administered orally.

Furthermore, there are attempts to utilize the antigen recognition function of lymphoid tissue in the airways to administer vaccines locally into the airways for disease prevention and treatment. Therefore, the importance of intratracheal administration is extremely great.

Based on the nature of the particles, intratracheal administration formulations can be classified into (1) formulations in which liquid droplets are deposited in the respiratory tract, and (2) formulations in which solid particles are deposited in the respiratory tract.

(1) is typically an aqueous solution containing a drug, atomized by a nebulizer and inhaled into the respiratory tract as tiny droplets. (2) can be further classified into aerosol formulations, in which solid drug particles are dispersed in fluorocarbons (CFCs) and stored in a pressurized container. When the container is released during use, they travel through the respiratory tract along with the CFCs, but after the CFCs quickly evaporate, they ultimately deposit as solid drug particles in the respiratory tract. (3) Powder formulations, in which the drug is stored as solid drug particles in a container and, upon use, the solid drug particles are sprayed directly from the container or by an applicator or inhaled into the respiratory tract, where they deposit as solid drug particles in the respiratory tract.

Both of these formulations are already in practical use, but (1) the liquid formulation requires a nebulizer and is therefore not portable. Also, (2) the fluorocarbon aerosol formulation is simple and widely used, but in recent years there has been a rapid movement to restrict its use due to the air pollution problem caused by fluorocarbons. Compared to the above two, (2) the powder formulation for intratracheal administration, which has been relatively slow to develop, has recently attracted particular attention.

As described above, administering a powder formulation for intratracheal administration requires a powder formulation container and an administering device. Hereinafter, the term "container" refers to the container in which the powder formulation is directly stored. After mixing and preparation, the powder formulation is stored in the container and preserved until use. Therefore, the container is typically sealed. Furthermore, the term "administrator" refers to a device that prepares the powder formulation from the container so that it can be administered into the respiratory tract. For example, the administering device holds the sealed powder formulation in an appropriate position and pierces it to allow the powder formulation contents to move from the container into the respiratory tract.

The container and dispenser are typically separate, but they can also be manufactured as a single unit. For example, a portion of the container can be removed during use to create a hole that allows the powder formulation contained therein to be transferred from the container into the respiratory tract.

The powder formulation, which has been transferred from the container to the airway by some operation using a dispenser or an integrated container-dispenser, is delivered to the airway by the user's (patient's) inhalation or by pressurized gas from a cylinder or some other device.

Containers and dispensers for powdered formulations for intratracheal administration are classified into two types: (1) unit-dose types, in which the amount of powdered formulation to be delivered to the airways at one time is pre-divided and stored in each container, depending on the amount of powdered formulation in the container; and (2) multi-dose types, in which multiple doses of powdered formulation are stored together in a container, with each dose being divided and delivered to the airways each time it is used from the stored container.

Many dispensers have been devised to accommodate these two types of storage methods. Examples include the unit-dose type powder drug dispensing device disclosed in Japanese Patent Publication No. 63-6024, the Pinhaler (registered trademark), Rotahaler (registered trademark), and Diskhaler (registered trademark) described in P.R. Byron, Respiratory Drug Delivery Journal, CRC Press, 1990, p. 169, and the multi-dose type Turbohaler (registered trademark) described in the same publication.

The shapes of containers for containing powder formulations vary depending on the storage method and the structure of the administering device. Conventional unit-dose containers include, for example, hard pharmaceutical capsules widely used for oral preparations, such as a disk-shaped component that can be loaded into a Diskhaler (trademark), a disposable container such as that proposed in W189101348. Multi-dose containers are also known, which are designed to fit into the structure of the administering device and allow a predetermined amount of the contents to be transferred from the administering device to the respiratory tract by some means. Any of these containers may be used in the present invention. They may also form part of the administering device. For example, they may be cylindrical and have a structure that allows a removable lid to be fastened to the administering device with a screw.

Meanwhile, materials used in containers containing conventional powdered formulations come into direct contact with the powdered formulation, even if the formulation is inhaled or aerosolized and the powdered formulation is administered into the respiratory tract, i.e., the human body, rather than the container itself. Therefore, considering safety and other factors, specific materials known to be suitable for such containers include gelatin, which is used to form pharmaceutical hard capsules widely used for unit-dose oral formulations; aluminum, which is molded into disks (see, for example, P.R. Byron, ed., op. cit., p. 169); and plastics, primarily polyolefins such as polyethylene, polypropylene, and polystyrene, which have been proposed as disposable containers. For multi-dose containers, materials include polyolefins such as polyethylene, polypropylene, and polystyrene; aluminum; and glass.

Known powder formulations housed in containers made of various materials include powders consisting of particles of the drug itself, which are administered to the respiratory tract and deposited there, where they are transferred locally or from the local area to the bloodstream to exert their systemic effects. These powders may be powders consisting of particles containing a drug, or powders consisting of particles of the drug alone or containing a drug mixed with particles of a suitable additive, such as lactose, mannitol, or microcrystalline cellulose.

Powder formulations for intratracheal administration require a small particle size, with the upper limit set at approximately 500 μm, to efficiently reach target sites within the respiratory tract and to increase the deposition area at those sites. The relationship between particle size and the target site within the respiratory tract has been investigated by many researchers, and while the reported values are not always consistent, it is believed that particles larger than 10 μm and up to approximately 500 μm are primarily deposited in the oral and nasal cavities, particles larger than 2 μm and up to 10 μm are primarily deposited in the trachea, bronchi, and bronchioles, and particles between 0.5 and 2 μm are primarily deposited in the alveoli (see "Latest Biopharmaceutics," edited by Awazu and Koizumi, Nankodo, 1991, p. 67). The particle sizes listed here naturally apply to both drug-only particles and drug-containing particles in powder formulations, and do not necessarily apply to additive particles.

The present inventors have continued to study the administration of powdered drugs to the nasal cavity, bronchi, alveoli, etc., based on the above-mentioned conventional powder formulation technology for intratracheal administration, but have encountered a major technical problem due to the fact that the above-mentioned powder formulations are fine particle powders.

Specifically, we discovered that while powder formulations are stored in the various containers mentioned above, or while they are loaded into an injector, they come into contact with the container due to vibration or other factors, resulting in drug particles or drug-containing particles adsorbing to and adhering to the container surface. Therefore, when administering a powder formulation to the respiratory tract, even if an attempt is made to introduce the powder formulation contained in the container into the respiratory tract by inhalation or by using pressurized gas in some other way, the particles adsorbed to and adhering to the container surface remain within the container and are not introduced or delivered to the respiratory tract.

This issue is not a problem for oral medications, which are administered with the container, even if the formulation adsorbs or adheres to the inner surface of the container. However, it is a major problem for powdered formulations for intratracheal administration, in which only the contents are administered to the body, without the container, and the amount delivered to the body is reduced, which can affect the therapeutic effect.

To address this issue, conventional methods have been investigated, such as adjusting drug or drug-containing microparticles, e.g., increasing the density of the microparticles, or pre-adhering or adsorbing the microparticles in a powder formulation to larger particles. These methods have proven effective in some cases, and have been shown to solve the problem, for example, with fluticosine nasal sprays. However, even with these methods, some drugs, such as those that adhere to gelatin or plastics, cannot be prevented from adhering to containers, and for highly adhesive peptides and proteins, adsorption to containers is unavoidable. Furthermore, particularly when powder formulations are kept dry to improve physicochemical stability, it is extremely difficult to prevent adsorption to containers using these methods.

Therefore, formulations for intratracheal administration that do not require the time-consuming preparation of fine particles, are applicable to a variety of drugs, and do not adsorb or adhere to the inner surface of the container are sought. Furthermore, formulations for intratracheal administration that do not adsorb or adhere to the inner surface of the container, even in a dry state, are particularly sought.

The concept of using hydroxypropyl methylcellulose or the like as a pharmaceutical container is well known. For example, Japanese Patent Application Laid-Open No. 61-100519 discloses a pharmaceutical hard capsule whose main component is hydroxypropyl methylcellulose.

Meanwhile, it is also known that various unit dose containers, including pharmaceutical hard capsules, and various multidose containers are used as containers for powdered formulations for intratracheal administration.

However, there have been no reports to date of significant adhesion or adsorption of herbal medicines or fine particles containing herbal medicines to the inner surface of containers in powder formulations for intratracheal administration. Furthermore, the inventors' discovery that this adhesion and adsorption phenomenon can be avoided by using a container containing hydroxypropyl methylcellulose or similar components is novel and could not have been predicted from the prior literature.

DISCLOSURE OF THE INVENTION The object of the present invention is to provide a formulation for intratracheal administration that prevents adhesion or adsorption of a drug or drug-containing particles to the inner surface of a container, thereby improving the amount of drug delivered from the container to the airways.

More specifically, an object of the present invention is to provide a formulation for intratracheal administration that does not reduce the amount of drug delivered from the container to the respiratory tract even when stored in a dry state.

According to the present invention, there is provided a powder formulation for intratracheal administration, which comprises a container containing at least one component selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, starch, hydroxypropyl starch, and sodium alginate, and a powder formulation for intratracheal administration.

As a result of extensive research aimed at solving the above-mentioned problems, the inventors surprisingly discovered that the above-mentioned problems can be overcome by storing a powder formulation for intratracheal administration in a container primarily composed of a cellulose derivative or analogue, i.e., a container composed of at least one component selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, guanylate, hydroxypropylguanylate, and sodium alginate, thereby completing the present invention.

The adhesion and adsorption of drug particles or drug-containing particles in a formulation contained in a container to the interior surface of the container is complex, involving many factors, including (1) the physical properties of the container, (2) the physical properties of the drug, (3) the physical properties of excipient particles coexisting with the drug particles or drug-containing particles, and (4) environmental factors such as humidity. Our research to date has demonstrated that, regardless of the physical properties or type of drug, drug particles or drug-containing particles alone or in the presence of excipients commonly used in powder formulations for intratracheal administration, when micronized to the particle size required for intratracheal administration, i.e., approximately 500 μm or less, inevitably adhere to and adsorb to commonly used containers, such as gelatin capsules, aluminum discs, and polyethylene containers, while they do not adhere to and adsorb to containers primarily composed of the cellulose derivatives and analogs of the present invention. We are also continuing to investigate why containers made of the cellulose derivatives and analogs of the present invention, i.e., hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, starch, hydroxypropyl starch, and sodium alginate, do not adhere or adsorb the above-mentioned microparticles. However, as mentioned above, the factors involved are complex and difficult to analyze. However, our experiments have confirmed that these cellulose derivatives and analogs do not become charged when in contact with drug particles or excipient particles, whereas gelatin, polyethylene, and other materials commonly used in containers do become charged, suggesting that electrostatic charging is one of the main factors.

BEST MODE FOR CARRYING OUT THE INVENTION The containers used in the present invention, which contain components such as hydroxypropyl methylcellulose, may be of the unit-dose type, in which the amount of powder formulation to be delivered to the respiratory tract at one time is pre-divided and stored, or of the multi-dose type, in which multiple doses of powder formulation are stored together and delivered to the respiratory tract each time a single dose of powder formulation is divided from the container by some means.

The unit-dose type may be in the form of a pharmaceutical hard capsule, a disk-shaped container with unit doses divided and stored in several locations on the disk surface, or any other suitable shape to fit the administering device, or a disposable container integrated with the administering device. The multi-dose type may be any suitable shape to fit the multi-dose administering device, and may have the necessary functions to be loaded into the multi-dose administering device when in use.

The proportion of hydroxypropyl methylcellulose or the like in a container made of hydroxypropyl methylcellulose or the like used in the present invention is subject to limitations imposed by the manufacturing method of the container (described below), but is preferably at least 70% by weight of the container, and more preferably 80% by weight or more. When two or more components are used, the total amount of the components is preferably within the above range.

Compounds that may be incorporated into the container containing the hydroxypropyl methylcellulose or other components used in the present invention include plasticizers, thickeners, thickener aids, and colorants, and specific examples include polyvinyl alcohol, polyethylene glycol, sorbitol, mannitol, sucrose, carrageenan, sodium chloride, potassium chloride, titanium oxide, lake color, and the like.

The containers used in the present invention are manufactured using at least one component selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch, hydroxypropyl starch, and sodium alginate. Among these components, hydroxypropyl methylcellulose is preferred. The hydroxypropyl methylcellulose used should preferably have a cellulose ether substitution rate of 15 to 30% by weight of methoxyl groups and 3 to 15% by weight of hydroxypropoxyl groups. Furthermore, a 2% aqueous solution with a viscosity of 2 to 20 cps at 20°C is preferred.

Furthermore, among the hydroxypropyl methylcelluloses used, those having a weight percentage of methoxyl groups of 19 to 30% and a weight percentage of hydroxypropoxyl groups of 4 to 12% are more preferred in terms of the substitution rate of the cellulose ether.

In terms of viscosity, the hydroxypropyl methylcellulose used is preferably one having a viscosity of 3 to 15 cps in a 2% aqueous solution at 20°C.

The containers used in the present invention, which are primarily made of hydroxypropyl methylcellulose, are manufactured in a manner similar to that used for gelatin hard capsules, which are commonly used for pharmaceutical hard capsules. Details of the manufacturing method are described in, for example, Japanese Patent Application Laid-Open Nos. 61-100519, 62-266060, 63-127757, and 3-9755, which are available for reference. It is readily apparent that these methods can be used to produce not only hard pharmaceutical capsules, but also all unit-dose and multi-dose containers that can be used for powder formulations for intratracheal administration.

The powdered formulation for intratracheal administration used in the present invention comprises a drug exhibiting a pharmacological action alone or a drug exhibiting a pharmacological action and an additive.

Drugs that exert their pharmacological effects locally in the airways include: Hydrocortisone, prednisone, prednisolone, triamcinolone Triamcinolone acetonide, dexamethasone, betamethasone Steroidal anti-inflammatory drugs such as beclomethasone dipropionate; Acetaminophen, zenacetin, aspirin, aminopyrine, sulpyrine, phenylbutaline, mefenamic acid, flufenamic acid, ibufenac, and ibuprofen , Alclofenac, diclofenac sodium, indomethacin, colchicine, brobenecid and other non-steroidal anti-inflammatory drugs; chymotrypsin, bromelaincera; enzymatic anti-inflammatory drugs such as peptase; antihistamines such as diphenhydramine hydrochloride, chlorpheniramine maleate, and flemastine; antiallergic drugs (antitussives, expectorants, asthma drugs) such as sodium cromoglycate, codine phosphate, and isoproterenol hydrochloride; tetracycline hydrochloride, leucomycin, fradioma isin, penicillin and its derivatives, antibiotics such as erythromycin, chemotherapy drugs such as sulfathiazole and nitromethacin; local anesthetics such as bensicaine; vasoconstrictors such as phenylephrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetaprine hydrochloride, trumazolin hydrochloride; cardiac stimulants such as digitalis and digoxin; vasodilators such as nitroglycerin and pabaverin hydrochloride; chlorhexidine hydrochloride, hexylresorcinol, dequalinium chloride, ethacrylamide Antiseptics such as benzodiazepine; enzymes such as lilithium chloride and dextranase; anticancer drugs such as 5-flufenacil; elastase inhibitors; salbutamol sulfate, procaterol hydrochloride, orsiveronimides; sympathomimetics such as prenaline and fenotrol hydrobromide; paracholinergic blockers (anticholinergics) such as ipratropium bromide and flutropium oxalate; expectorants such as diacetylcysteine sodium and bromhexine; and mucosal lubricants such as amproxol hydrochloride.

In addition, drugs that exert pharmacological effects are absorbed into body fluids such as blood through the respiratory tract and exert systemic pharmacological effects, such as peptides and proteins (i.e., polypeptides) that have various physiological activities.

Polypeptides with a molecular weight in the range of 300 to 300,000 are preferred because they are easily absorbed through the respiratory mucosa. Molecular weights in the range of 1,000 to 150,000 are particularly preferred. Specific examples of preferred physiologically active polypeptides include the following: Examples include peptide hormones such as insulin, angiotensin, pleuropneumonia, desmopressin, febrile renal failure, protirelin, luteinizing hormone-releasing hormone, corticotropin, prolactin, thyrotropin, luteinizing hormone, calcitonin, kallikrein, luteinizing hormone-releasing hormone, glucagon, oxytocin, gastrin, secretin, serum gonadotropin, growth hormone, erythromycin, angiotensin, urogastrone, renin, ribomodulin, calmodulin, and human atrial natural polypeptide (hANP), as well as their chemically modified compounds or components; biologically active proteins such as interferons, interleukins, transferrin, histaglobulins, macrocortins, and blood clotting factors; and enzyme proteins such as lysozyme and urokinase.

In addition, examples of drugs that exert pharmacological effects include vaccines that utilize the antigen recognition function of lymphoid tissue in the respiratory tract, such as pertussis vaccine, diphtheria vaccine, tetanus vaccine, and influenza vaccine, as well as vaccines such as lymphocytosis factor and filamentous erythrocyte agglutination factor.

Among the drugs exhibiting the above-mentioned pharmacological effects that can be used in the present invention, drugs for which mechanical loss due to adhesion or adsorption to the inner surface of the container can result in a substantial loss of dosage, i.e., highly active drugs with small dosages, are preferred. The amount of adhesion or adsorption to the inner surface of the container varies depending on the contact area between the container and the formulation. For example, when a 5-10 μm particle size of beclomethasone dipropionate powder is placed in a No. 2 gelatin capsule, the amount of adhesion or adsorption is approximately 10 μg. It goes without saying that the amount of loss due to adhesion or adsorption will vary depending on the container shape, the size of the container (whether unit dose or multidose), and other factors. However, assuming a maximum loss of 100 μg per dose, based on the example of beclomethasone dipropionate mentioned above, the maximum dosage at which this value is considered to be a substantial loss of dosage is approximately 2 mg per dose. Therefore, although not limited, drugs with dosages of approximately 2 mg or less per dose are preferred.

Specifically, these include steroid anti-inflammatory drugs, sympathomimetics, parasympathetic blockers, peptides, proteins, and vaccines.

Furthermore, adhesion and adsorption to the container are particularly pronounced in a dried state, making this method particularly suitable for drugs that are dried for stabilization. Examples of such drugs include peptides, proteins, and vaccines.

The additives used in the powder formulation for intratracheal administration of the present invention together with the drug exhibiting a pharmacological effect may be any additives that have been or can be used in powder formulations for intratracheal administration. Examples of such additives include excipients, and specific examples include one or more selected from the group consisting of cellulose ethers, water-absorbent and water-insoluble bases, sugars, amino acids, etc.

Cellulose ethers are cellulose derivatives in which multiple hydroxyl groups of cellulose are at least partially etherified, and include, for example, lower alkyl ethers, lower hydroxyalkyl ethers, and lower carboxyalkyl ethers of cellulose.

The ether group does not have to be of one type; for example, the cellulose ether may have two or more types of ether groups in the molecule, such as both a lower alkyl group and a lower hydroxyalkyl group. Of these, lower alkyl ethers or lower hydroxyalkyl ethers of cellulose are preferred. Here, "lower alkyl" refers to an alkyl group having 5 or fewer carbon atoms, preferably 3 or fewer carbon atoms.

Examples of the cellulose ethers include methyl cellulose, ethyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, and hydroxypropyl methyl cellulose. Of these, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose are particularly preferred.

As the cellulose ether, for example, one having a viscosity of 3 to 100,000 centipoise, more preferably 3 to 10,000 centipoise, and particularly preferably 6 to 6,000 centipoise in a 2 wt % aqueous solution at 20°C is preferably used.

As cellulose ethers, for example, those with a degree of ether substitution of 0.1 to 6.0, particularly 0.4 to 4.6, are preferably used. Here, the degree of ether substitution refers to the average number of ether groups per glucose unit constituting cellulose for the three hydroxyl groups that one unit has.

Examples of water-absorbent, poorly water-soluble bases include water-absorbent, poorly water-soluble celluloses such as crystalline cellulose, α-cellulose, and cross-linked sodium carboxymethylcellulose; water-absorbent, poorly water-soluble starches such as hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin, and pectin; water-absorbent, poorly water-soluble proteins such as gelatin, casein, and sodium caseinate; water-absorbent, poorly water-soluble gums such as gum arabic, gum tragacanth, and glucomannan; and cross-linked vinyl polymers such as polyvinyl polypyrrolidone, cross-linked polyacrylic acid and its salts, cross-linked polyvinyl alcohol, and polyhydroxyethyl methacrylate. Of these, water-absorbent, poorly water-soluble celluloses are preferred, with crystalline cellulose being particularly preferred.

Examples of sugars include glucose, mannitol, lactose, fructose, and dextran.

Examples of amino acids include glycine and alanine. In addition to these excipients, dispersing aids, lubricants, stabilizers, etc. may also be added as needed.

The additive and the drug that exerts a pharmacological effect may exist as separate particles or may comprise the same particle. In the former case, the additive and drug are mechanically mixed to form a formulation, while in the latter case, the additive and drug are dispersed or dissolved in an appropriate solvent, followed by spray drying to form a formulation.

The formulation for intratracheal administration of the present invention is produced from the above-described container and powder formulation (containing either the drug alone or the drug and additives), and the particle size varies depending on the intended site of drug delivery within the respiratory tract.

As mentioned above, the location within the respiratory tract that a drug reaches depends on the particle size of the formulation. It is believed that particles larger than approximately 10 μm and smaller than approximately 500 μm are deposited primarily in the oral cavity and nasal cavity, particles larger than 2 μm and smaller than 10 μm are deposited primarily in the trachea, bronchi, and bronchioles, and particles between 0.5 and 2 μm are deposited primarily in the alveoli. Therefore, by adjusting the particle size of the powder formulation, it is possible to efficiently deliver drugs to the desired location.

First, to deliver a drug to the oral or nasal cavity, the particles of the powder formulation stored in the container of the present invention may be adjusted to a size greater than 10 μm and less than 500 μm. A topical drug such as a nasal allergy treatment may be prepared by blending, in a blender, the steroid anti-inflammatory drug beclomethasone dipropionate milled to a particle size greater than 10 μm and less than 500 μm with the additive hydroxypropyl cellulose having a particle size greater than 10 μm and less than 500 μm.

In this case, to prolong the medicinal effect, additives blended with the active ingredient are preferably cellulose ethers such as hydroxypropyl cellulose, as exemplified above. Other topical medications include other steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, enzymatic anti-inflammatory drugs, antihistamines, antiallergic drugs, and vasoconstrictors. Among similar powder formulations, systemic medications include nasal formulations that penetrate the bloodstream through the nasal mucosa and exert a systemic effect. For example, calcitonin with a particle size of greater than 108 μm and less than 500 μm, such as salmon calcitonin, is obtained by blending in a mixer with microcrystalline cellulose with a particle size of greater than 10 μm and less than 500 μm. In this case, to ensure rapid onset of effect and good absorption, additives blended with the herbal medicine are preferably water-absorbent, poorly water-soluble bases, as exemplified above. Other systemic medications include peptides other than calcitonin, polypeptides such as proteins, and vaccines.

Next, in order to deliver a drug to the trachea, bronchi, bronchioles, and alveoli, the particle size of the drug particles or drug-containing particles in the powder formulation contained in the container of the present invention may be adjusted to a range of 10 μm to 0.5 μm.

It is not necessary for all particles to fall within this range, but the greater the total amount within this range, the greater the amount delivered to the trachea, bronchi, bronchioles, and alveoli.

When particles of additives such as excipients are present in addition to drug particles or drug-containing particles, the additive particles do not need to be adjusted to 10 μm to 0.5 μm, but may be adjusted to 10 μm or larger so as to be trapped in the oral or nasal cavity.

The drug particles, drug-containing particles, and additive particles adjusted to such particle sizes are mixed in a conventional manner to form a powder formulation.

Among such powder formulations, topical medications include, for example, antiasthmatics, which can be obtained by mixing the steroid anti-inflammatory drug beclomethasone dipropionate with the additive hydroxypropyl cellulose, or by spray-drying to produce microparticles of hydroxypropyl cellulose containing beclomethasone dipropionate with a particle size of 10 to 0.5 μm. Other topical medications include other steroid anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, enzyme anti-inflammatory drugs, antiallergic drugs, antihistamines, elastase inhibitors, sympathomimetics, parasympathetic nerve blocking agents, solubilizers, and mucosal swelling agents.

Similar formulations include pulmonary formulations for systemic medications, which penetrate the alveolar mucosa into the bloodstream and exert their systemic effects. These formulations are obtained, for example, by mixing insulin with glucose or spray-drying hydroxypropyl cellulose microparticles containing insulin with a particle size of 10 to 0.5 μm. Other systemic medications include polypeptides such as other peptides and proteins.

The additives used in these powder formulations to be delivered to the trachea, bronchi, bronchioles, and alveoli are preferably non-irritating and water-soluble, such as sugars, amino acids, and water-soluble cellulose ethers.

The formulation of the present invention is administered into the respiratory tract via the nasal or oral cavity, but the power source required to introduce the powder formulation of the present invention from the container into the respiratory tract via both knees may be the patient's own inhalation (inhalation) or a power source other than the patient's inhalation, such as a rubber bulb (nebulization).

Thus, the powder formulation for intratracheal administration used in the present invention is contained in a container made of the aforementioned components, such as hydroxypropyl methylcellulose, used in the present invention, and the shape of the formulation is selected to match the structure of the administering device, so the structure of the administering device is important.

In principle, there are no limitations on the structure of the dispenser used to administer the powder formulation for intratracheal administration of the present invention, and any conventionally used or proposed dispenser (drug dispenser) for powder formulation for intratracheal administration may be used. Examples of unit-dose containers include a powdered drug dispenser (JP Patent Publication No. 63-6024) that corresponds to a hard pharmaceutical capsule container, as well as the Pinhaler (registered trademark), Rotahaler (registered trademark), and Diskhaler (registered trademark).

Additionally, examples of multi-dose containers include Turbohaler (registered trademark).

INDUSTRIAL APPLICABILITY As described above, according to the present invention, when a powder formulation for intratracheal administration, which is contained in a container made of components such as hydroxypropyl methylcellulose, is administered into the respiratory tract using the above-described administering device, the amount of powder formulation that adheres to and is adsorbed onto the inner surface of the container is less than when a powder formulation for intratracheal administration contained in a conventional container is administered into the respiratory tract using the above-described administering device. This results in a significantly greater amount of powder formulation actually delivered to the respiratory tract, which is of great therapeutic significance.

The present invention will be explained in more detail below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Examples 1-16, Controls 1-64 Powder formulations for intratracheal administration to containers containing hydroxypropylmethylcellulose as the main ingredient The following experiments were conducted to demonstrate the low adhesiveness and adsorption of the formulations.

(1) Manufacturing of a box for measuring adhesion and adsorption amounts to various container materials. A cardboard box with a square bottom measuring 2 cm on each side and a rectangular parallelepiped shape 1 cm high, with one bottom open, was made. The five inward-facing surfaces (four sides and one bottom) of the box were covered with the thin film material described in section (2) below using Aron Alpha (Toa Gosei Chemical Division).

(2) Preparation of Thin-Film Materials to be Attached to the Inner Surface of the Adhesion/Adsorption Measurement Box Five types of materials, including materials primarily composed of hydroxypropyl methylcellulose according to the present invention, were prepared as follows:

Material A: Hydroxypropylmethylcellulose (Shin-Etsu Chemical Co., Ltd., TC-5R: 28-30% by weight of methoxyl groups, hydroxypropoxyl groups).

Material B: A 0.1 mm-thick thin film consisting of 93 parts of 2% aqueous solution (7-12% by weight, viscosity at 20°C: 6 cps), 1 part by weight of carrageenan (Wako Pure Straw), 1 part by weight of potassium chloride (Wako Pure Straw), and 5 parts by weight of water. (Dissolved in excess water, spread on a flat plate, and dried to form a uniform film.) Material B: A 0.1 mm-thick thin film consisting of 95 parts by weight of gelatin (Wako Pure Chemical Industries) and 5 parts by weight of water. (The material was dissolved in excess water, spread on a flat plate, and then dried to form a uniform film.) Material C: Polypropylene sheet (Tsuko sheet used as is) Material D: Aluminum foil (Pak foil used as is) Material E: Regular thin plate glass (3) Preparation of a drug-containing powder formulation for intratracheal administration. The drug, base, and lubricant listed in Table 1 were mixed and prepared according to the method listed in the same table to prepare a powder formulation for intratracheal administration.

(4) Measurement Method for Adhesion and Adsorption Amounts 100 mg of each intratracheal formulation prepared in (3) was placed in the measurement box described in (1) lined with the materials described in (2). The box was shaken sideways for 1 hour on a shaker to allow contact between the powder formulation and the materials. During shaking, the open top surface was covered with a lid to prevent scattering. (These experiments were conducted at 25°C/40% RH.) After shaking, the lid was removed and the contents were removed. The powder formulation was expelled by gently tapping the box with a spatula until no powder formulation was visible to the naked eye on the bottom or sides. The expelled powder formulation was collected, and the drug content was measured by high-performance liquid chromatography. The adhesion and adsorption rates to the inner surface of the box were calculated from the amount initially placed in the box. Table 2 shows the results for Examples 1 to 16, which combined the container material of the present invention with a powder formulation, and Table 3 shows the results for Control Examples 1 to 64, which combined a conventional container material with a powder formulation.

(Table 1 footnote) 1) Sigma 8) Sigma 2) Same as above 9) Same as above 3) Peptide Research Shinko 10) Fat Chemical Avicel PHIOI 4) Sigma 1 1) 8) Yokasei 5) Same as above 12) Nippon Soda RPC-H6) Same as above 13) Maigret 7) Same as above 14) Shin-Etsu Chemical TC-5R. In Table 1, the parentheses indicate the drug content in 30+ng of powder formulation for nasal intranasal administration and in 5 mg of powder formulation for inhalation administration.

The content of magnesium stearate in the powder formulation was 0.5% by weight. The formulation was prepared as follows:

a) A predetermined amount of drug milled to a particle size of 46-49 μm was taken, and a base in which 90% or more by weight of the particles had a particle size of 46-149 μm was added, and the mixture was mixed in a small V-type blender until uniform. Finally, 0.5% of magnesium stearate was added to obtain a uniform powder formulation for intranasal administration.

b) A predetermined amount of drug, prepared to a particle size of 0.5-10 μm, was added to a base in which 90% by weight or more of the particles had a particle size of 46-49 μm, and the mixture was mixed in a small V-type blender until uniform. Finally, 0.5% of magnesium stearate was added to obtain a uniform powder inhalation formulation (inhalant) for intratracheal administration.

C) A predetermined amount of drug and base was dissolved in a water-based solvent (ethanol was added if necessary) and spray-dried to prepare a fine particle powder. Finally, 0.5% magnesium stearate was added to obtain an inhalable powder formulation (inhalant) for intratracheal administration.

The particle size distribution of the powder preparation obtained by the preparation method described in C) above was 80% or more of the particles in the range of 0.5 to 10 μm.

Tables 2 and 3 show that the adhesion and adsorption of powder formulations for intratracheal administration to containers made primarily of hydroxypropyl methylcellulose are less than those to containers made of gelatin, polypropylene, aluminum foil, or glass.

Examples 17-2L, Control Examples 65-69 30 mg of each of the powder formulations (1), (2), (3), (4), and (5) listed in Table 1 above was filled into pharmaceutical hard capsules containing hydroxypropylmethylcellulose as the main ingredient (composition: hydroxypropylmethylcellulose, Shin-Etsu Chemical, TC-5R, 93 parts by weight of carrageenan, 1 part by weight of potassium chloride, 1 part by weight of water, 5 parts by weight). After storage at 25°C (155%RH) for two weeks, the powder formulation was sprayed using a powdered drug dispenser (Japanese Patent Publication No. 63-6024) until the powder formulation was no longer visible to the naked eye. The hard capsules were then removed, and the remaining herbs on the capsule inner surface were measured by HPLC to calculate the adhesion and adsorption rates to the capsule inner surface. A similar experiment was also conducted after storing the capsules in a silica gel desiccator for two weeks. (Examples 17-21) Simultaneously, 30 mg of each of the powder formulations (1), (2), (3), (4), and (5) listed in Table 1 above was filled into pharmaceutical capsules containing gelatin as the main ingredient (composition: gelatin, 95 parts by weight; water, 5 parts by weight), and experiments similar to those in Examples 17-21 were conducted. (Control Examples 65-69) The results are shown in Table 4.

Table 4 shows that when powder formulations for intratracheal administration filled in capsules primarily composed of hydroxypropyl methylcellulose are sprayed from a powder drug delivery device, the proportion of powder remaining inside the capsule is less than when the formulations are filled in gelatin capsules and sprayed simultaneously, and the amount of powder adsorbed is not affected by drying. Some gelatin capsules were observed to crack when dried.

Examples 22, 23, Control Examples 70, 71 5 mg of powder formulations (1) and (2) listed in Table 1 were filled into pharmaceutical hard capsules containing hydroxypropylmethylcellulose as the main ingredient, as in Examples 17-21. The capsules were then punctured using a powder drug dispensing device, as in Examples 17-21. A suction pump was then connected to the device, and the capsule contents were aspirated at 60 liters per minute. The amount of active ingredient remaining on the capsule surface was then measured in the same manner, and the adhesion rate to the capsule surface was calculated. (Examples 22, 23) Similar experiments were also conducted using gelatin capsules filled with the same powder formulations (1) and (2), and the adhesion rate to the capsule surface was calculated.

(Control Examples 70 and 71) The results are shown in Table 5.

Table 5 shows that when a powder formulation for intratracheal administration filled in a capsule containing hydroxypropyl methylcellulose as the main ingredient is inhaled in the same manner as human inhalation, the proportion of the powder remaining inside the capsule is less than when the formulation is filled in a gelatin capsule and inhaled in the same manner.

Examples 24-28 In the same manner as in Examples 1-16, thin film materials consisting of F, G, H, I, and J were prepared.

Material F: A 0.1% thick thin film consisting of 951 parts by weight of methylcellulose (Shin-Etsu Chemical, Metrose 5M15) and 5 parts by weight of water (dissolved in excess cold water, spread on a flat plate, and dried to form a uniform thin film). Material G: A 0.1% thick thin film consisting of 951 parts by weight of hydroxypropyl cellulose (NaOH HPC-M) and 5 parts by weight of water. 11!101 thin film (dissolved in excess cold water, spread on a plate, and dried to form a uniform thin film). Material H: 0.111 1/2 l thin film consisting of 95 parts by weight of starch (corn starch, Nippon Shokuhin Kako 'R') and 5 parts by weight of water (solubilized in boiling water, spread on a plate, and dried to form a uniform thin film). Material I: 0.10 mm thick thin film consisting of 95 parts by weight of hydroxypropyl starch (Freund Corporation, HPSIOI (W)) and 5 parts by weight of water (solubilized in boiling water, spread on a plate, and dried to form a uniform thin film). Material J: 0.1 mm thick thin film consisting of 95 parts by weight of sodium alginate (Kimitsu Chemical) and 5 parts by weight of water (dissolved in cold water, spread on a plate, and dried to form a uniform thin film).

The same experiments as in Examples 1 to 16 were conducted on these F-J materials and the powder formulations (I) of Examples 1 to 16, and the adhesion and adsorption rates of (I) to F-J were measured.

The results are shown in Table 6.

Table 6 shows that the adhesion and adsorption of powder formulations for intratracheal administration to containers containing methylcellulose, hydroxypropyl cellulose, starch, hydroxypropyl phosphate, and sodium alginate as the main ingredients are low, similar to those to containers containing hydroxypropyl methylcellulose as the main ingredient.

Claims (1)

[Claims] 1. A formulation for intratracheal administration, comprising a powder formulation for intratracheal administration housed in a container comprising at least one component selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, starch, hydroxypropyl starch, and sodium alginate. 2. The formulation of claim 1, wherein the component accounts for at least 80% by weight of the container. 3. The formulation for intratracheal administration of claim 1 or 2, wherein the component is hydroxypropyl methylcellulose. 4. The formulation for intratracheal administration of claim 1, wherein the container is molded to be loaded as a unit dose or multi-dose into an administering device for administering powder into the respiratory tract. 5. The formulation for intratracheal administration of claim 4, wherein the container is a pharmaceutical hard capsule and is loaded as a unit dose into an administering device for administering powder into the respiratory tract. 6. The formulation for intra-respiratory administration according to claim 1, wherein the container is integrated with an administering device for administering the powder into the respiratory tract and is disposable. 7. The formulation for intra-respiratory administration according to any one of claims 1 to 6, wherein the powder formulation for intra-respiratory administration is a powder formulation that is inhaled through the nasal cavity and deposited therein. 8. The formulation for intra-respiratory administration according to any one of claims 1 to 6, wherein the powder formulation for intra-respiratory administration is a powder formulation that is sprayed into the nasal cavity and deposited therein. 9. The formulation for intra-respiratory administration according to any one of claims 1 to 6, wherein the powder formulation for intra-respiratory administration is a powder formulation that is inhaled through the oral cavity and deposited in the oral cavity, pharynx, larynx, trachea, bronchi, bronchioles, or alveoli. 10. The powder formulation for intratracheal administration according to any one of claims 1 to 6, which is a powder formulation that is sprayed into the oral cavity and deposited in the oral cavity, pharynx, larynx, trachea, bronchi, bronchioles, and alveoli. 11. The powder formulation for intratracheal administration according to any one of claims 1 to 6, which is a powder formulation containing a drug selected from the group consisting of antiallergic drugs, steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, enzymatic anti-inflammatory drugs, antihistamines, antibiotics, disinfectants, chemotherapy drugs, elastase inhibitors, local anesthetics, vasoconstrictors, cardiac inonics, vasodilators, antineoplastic drugs, sympathomimetics, parasympatholytic drugs, sputum lytics, mucosal lubricants, peptides, proteins, and vaccines. 12. The powder formulation for intratracheal administration according to claim 11, wherein the powder formulation for intratracheal administration comprises an excipient administered simultaneously with the drug, the excipient being selected from the group consisting of cellulose ethers; water-absorbent, poorly water-soluble celluloses; water-absorbent, poorly water-soluble proteins; water-absorbent, poorly water-soluble gums; water-absorbent, poorly water-soluble cross-linked vinyl polymers; sugars; and amino acids. 13. The powder formulation for intratracheal administration according to any one of claims 1 to 6, wherein the powder formulation for intratracheal administration is a powder formulation comprising a drug selected from the group consisting of steroidal anti-inflammatory drugs, sympathomimetics, parasympatholytics, peptides, and proteins. 14. 14. The powder formulation for intratracheal administration according to claim 13, wherein the excipient is selected from the group consisting of water-absorbent, poorly water-soluble celluloses; water-absorbent, poorly water-soluble starches; water-absorbent, poorly water-soluble proteins; water-absorbent, poorly water-soluble gums; and water-absorbent, poorly water-soluble crosslinked vinyl polymers.