JPH0984855A - Aerosol preparation for administer medicine to rectum or vagina - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new preparation which is easily and hygienically applicable to a medicine-administering part and is quick and effective in absorption of medicament through rectum or vagina or action thereof on rectum or vagina. SOLUTION: In this aerosol preparation, an aerosol container 3 having a valve 2 to be opened or closed by an actuator part 1 is sealed with a medicine 4 containing medicament that can be administered to a rectum or a vagina together with a jetting agent 5. A nozzle 6 is attached to the actuator part 1 with an outside shape suitable for the insertion thereof into the rectum and the vagina. The valve 2 is opened by the operation of the actuator part 1 so that the medicine 4 is jetted from the nozzle 6 by a pressure of the jetting agent 5 to administer the medicament to the rectum or the vagina. The valve herein used is preferably a continuous flow valve. The medicine is jetted in the form of mist, foam, powder and the like.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to formulations for administering drugs rectally or vaginally.

[0002]

2. Description of the Related Art Conventionally, suppositories, soft capsules, ointments and the like have been used clinically as pharmaceutical preparations that can be administered rectally or vaginally. Drug administration to the rectum and vagina is intended to give a systemic effect through the rectum or vagina as an absorption route, or to give a local effect to the anus, rectum, or vagina itself. Is included.

[0003]

However, since the above-mentioned preparation has a large amount of the base, it has a large size and it takes a long time to release the active ingredient. Furthermore, in the case of solid suppositories and capsules, this is usually applied by inserting it with a finger to a certain depth in the organ, which gives an unsanitary impression and is therefore avoided from use. Tend.

The object of the present invention is to solve the above-mentioned problems, to administer a drug rectally or to the vagina, the amount of the base can be freely selected, and the administration site is easy and hygienic. To provide a novel preparation applicable to

[0005]

Means for Solving the Problems The drug administration method of the present invention has the following features. (1) A drug that can be administered to the rectum or vagina is contained in an aerosol container having an actuator part provided with a nozzle having an external shape suitable for insertion into the rectum or vagina, and a valve opened and closed by the actuator part. A drug is enclosed together with a propellant, the valve is opened by the operation of the actuator portion, and the drug is ejected from a nozzle by the pressure of the propellant, which is for rectal or vaginal drug administration. Aerosol formulation.

(2) The aerosol formulation for rectal or vaginal drug administration according to the above (1), wherein the valve is a metered valve.

(3) The aerosol preparation according to the above (1) or (2), wherein the medicine sprayed from the nozzle is in the form of mist, foam or powder.

[0008]

The present invention is to administer a drug in the form of an aerosol formulation by injecting it into the rectum or vagina and exhibiting the following actions. (1) It is possible to freely use a drug having a low content of the base material, and the drug can be directly sprayed onto the administration site, so that the drug is quickly absorbed or acts on the affected site. (2) The valve and injection mechanism can be selected according to the prescription content and drug, and the mode of the drug when injected can be freely set to atomized, foamy, or powdered. Also, the use of a metered valve allows easy and accurate administration of the drug in exactly the required amount. (3) Since it can be applied without touching the anus, it can be used easily and hygienically. (4) Since the drug is enclosed in the aerosol container at a pressure higher than the atmospheric pressure, it is possible to prevent contamination by contaminants from the outside and deterioration due to moisture in the atmosphere. (5) It is possible to inject the drug together with the propellant. The inside of the rectum or vagina is usually in a state in which inner walls are in close contact with each other and a space is not formed, except when gas is present. When the propellant is injected together with the drug, the propellant becomes gas and expands in the rectum or vagina,
A favorable space for drug administration is ensured and a favorable condition for spraying the drug is obtained. Therefore, it is possible to easily and freely choose to apply the drug as thin as necessary to the inner wall surface of the rectum or vagina.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Next, the present invention will be described in detail with reference to the drawings. FIG. 1 shows an example of the structure of an aerosol formulation for rectal or vaginal drug administration according to the present invention.
As shown in the example of the figure, in the aerosol preparation according to the present invention, a drug 4 is contained as a so-called undiluted solution in a aerosol container 3 having an actuator section 1 and a valve 2.
And the actuator part 1 is provided with a nozzle 6 having an external shape suitable for insertion into the rectum or vagina, and the drug 4 contains a drug that can be administered to the rectum or vagina. Is. In the figure, only valves, actuators, and nozzles are hatched to show cross sections. With such a structure, the nozzle 6
After inserting into the rectum or vagina, the actuator 1 is operated to open the valve 2 so that the pressure of the propellant in the aerosol container causes the drug to be ejected together with the propellant from the nozzle 6 into the organ. The drug is administered to.

In the aerosol formulation for rectal or vaginal drug administration of the present invention, as to the mechanism for injecting the drug, all the configurations for injecting available in the known aerosol formulation can be used.

The aerosol container may have a known structure and material. The preferred structure of the aerosol container is as follows. Side seam can consisting of a cylindrical body, top lid, and bottom lid. A seamless can consisting of a body and a bottom lid. A monoblock can made by press-molding aluminum etc. into a seamless piece. Examples of the material forming the aerosol container include metal (tin, aluminum, etc.), glass, resin and the like. There is no limitation on the size of the aerosol container, and a preferred size may be selected according to the application, such as a size for permanent installation in a home or a medical field, a size for carrying, and the like.

The valve may be an opening / closing mechanism which is attached to open the contents sealed in the aerosol container at a high pressure to the outside and which is opened / closed by the operation of the actuator section. Good. FIG. 2 schematically shows an example of a general basic structure of the valve. As shown in the figure, the stem 21 has an actuator portion (not shown).
The stem hole 22 closed by the gasket rubber 23 is opened and communicated with the inside of the container by being pressed in the direction of the inside by the container, and the contents are pushed up by the valve through the dip tube 24 and discharged to the outside of the container. To be done.

As another example of the valve, as shown in phantom black in FIG. 2, for example, a gas phase hole 26 communicating with the inside of the container is provided in the housing 25, and the gas phase portion inside is taken into the flow channel together with the drug. There is a valve with a vapor phase hole that improves atomization.

A metering valve is mentioned as a particularly preferable valve for the aerosol preparation of the present invention. The metering valve has a metering chamber 27 as schematically shown in FIG. 3 as an example of its basic structure. With the opening operation of the valve, the fixed amount chamber 27 is first hermetically isolated from the inside of the container and becomes a closed chamber for holding a prescribed amount of the drug at the internal pressure in the aerosol container.
Next, the stem hole 22 is opened to the outside of the container, and only the drug in the metering chamber is ejected. By using this metering valve, a prescribed amount of the drug can be easily injected into the organ. The injection amount of the metering valve per injection is usually 10 μl to 500 μl, and particularly 20 μl to
200 μl is preferred for rectal or vaginal administration.

The aerosol preparation according to the present invention may be used in a state where the valve is on the upper side or a state where the valve is on the lower side (that is, the container is inverted). Since the present invention is applied to the rectum and vagina, the mode in which the container is used in an inverted state may be easy for the user to handle. Examples of the aerosol container that can be used in an inverted state include a container having the valve with a vapor phase hole, and a weight that is attached to the tip of the container using a flexible dip tube that can be sufficiently bent. Whatever direction the aerosol container is used in, the tip of the dip tube always moves below the container by the weight so that the dip tube is always immersed in the contents.

The actuator portion is a portion that exerts a force to open and close the valve, and has a flow passage that penetrates the inside, and one end of the flow passage is connected to the stem of the valve and the other end. The end portion, that is, the outlet portion has a nozzle described later. The shape of the actuator main body excluding the nozzle is preferably designed according to the opening / closing operation of the valve and is easy to operate, and the push button is generally used. The direction in which the content is sprayed is not limited to the axial direction of the aerosol container. A mode of spraying in a direction perpendicular to the axial direction of the container (direction in which the actuator is pushed) like a general spray, or a mode of spraying outward along the axial direction of the container (that is, discharged from the stem). In the same direction), in the opposite direction (that is, in the direction of being guided to the bottom by the actuator or nozzle along the outside of the container), or in any direction between them. The structure may be such that the injection is performed toward one side or the structure can be changed in any direction.

In many cases, the actuator portion is projected upward such as a push button. As a measure for protecting the push button, a cap is separately provided, or the push button is incorporated in the cap. It suffices to take preferable publicly known measures based on legal regulations, such as an aspect in which the shape does not protrude. Further, it may be a mode in which the actuator part is integrally or disassembleably incorporated in a decorative case that encloses the entire aerosol container, and only the used aerosol container can be replaced. Such an incidental structure may be freely added in consideration of appearance and usability.

The nozzle has an external shape suitable for insertion into the rectum or vagina, and is provided so as to project from the actuator portion. Further, the actuator portion itself may have an external shape suitable for insertion into the rectum or vagina, and the nozzle and the actuator portion may have an integral structure in which the outer shapes cannot be clearly distinguished. Considered to be an actuator section with a nozzle shaped to fit into the rectum or vagina. The external shape of the nozzle is not particularly limited, and examples thereof include a tubular material having a cylindrical shape, a conical shape, or the like. Further, it may be a tubular object which can be freely bent and whose injection direction can be changed. Regardless of whether it is applied to the rectum or vagina, a preferable shape is a shape in which the distal end portion of the tubular article is provided with sufficient roundness or taper so that it can be smoothly inserted into the organ. The external shape of the nozzle when applied in the rectum may be a cylindrical or conical tubular object having a sufficient roundness or taper at the tip as described above, for example, a conventionally known enema device. Examples include a shape conforming to the tip shape. The length of the nozzle protruding from the actuator part is not limited,
20m so that the contents can be sprayed to an appropriate site in the rectum
It is suitable to set it to about m to 80 mm. The external shape of the nozzle when applied to the vagina may be a cylindrical or conical tubular object having a sufficient roundness or taper at the tip as described above. For example, conventionally known vaginal washing A shape similar to the tip shape of the tool may be used. The length of the nozzle protruding from the actuator part is not limited as in the case of the rectum, and it is suitable to be about 20 mm to 80 mm so that the content can be sprayed to an appropriate site in the organ.

The nozzle may be of a structure that can be easily replaced so as to be disposable. When making the nozzle replaceable, there are a mode in which the actuator part is fixed and only the nozzle is replaced, and a mode in which the actuator part and the nozzle are both replaced as a simple integrated structure. Further, the nozzle may have a multi-layered tubular structure, and only the surface layer portion in contact with the living organ may be replaced. The structure relating to the attachment / detachment of the replacement part of the nozzle is not limited, and examples thereof include those having a simple screw connection, attachment / detachment with screws, and a seal structure using a gasket in the fitting part.

The nozzle may be provided with various well-known nozzle hole structures such as a straight nozzle and a break-up nozzle for the purpose of enlarging the spray angle and refining the particle size. The portion to which the structure of the nozzle hole is given may be freely determined such as the tip outlet portion of the nozzle or the actuator portion side portion of the nozzle. Furthermore, the nozzle hole structure may be provided at the outlet of the actuator portion, and the nozzle itself may be a simple tubular object only for insertion into an organ. The form of the drug sprayed from the nozzle is preferably a mist form, a foam form, a powder form, a stream form, an ointment form, a cream form, or a paste form, depending on the prescription content and the drug. The mode of the drug injected from these nozzles can be selected by the structure of the nozzle alone, the structure of the nozzle and the valve working in cooperation, and the structure of the entire aerosol formulation containing the propellant and the drug. is there.

The propellant and the medicine contained in the aerosol container may be those which are contained in a known ejectable form. This will be described separately according to the mode of the propellant. The propellant can be classified into a liquefied gas propellant and a compressed gas propellant.

When the propellant is a liquefied gas propellant, the propellant contained in the aerosol container and the form of the drug are as follows. A two-phase system consisting of an upper gas phase propellant and a lower liquid phase agent. FIG. 1 is an example of a two-phase system. A three-phase system consisting of an upper gas phase, a middle liquid phase (lipophilic) two-phase propellant, and a lower liquid phase (hydrophilic) drug. In the above, the propellant in the middle liquid phase and the drug in the lower liquid phase are emulsified. It consists of a two-phase propellant consisting of an upper gas phase and a middle liquid phase (lipophilic), and a fine powder of an insoluble drug dispersed in the liquefied gas of the middle liquid phase. True 3 of solid phase
Embodiments called suspension systems that are phases. In this mode, the liquefied gas is vaporized at the same time as the injection, and an aerosol of fine drug particles is obtained.

As the liquefied gas type propellant, chlorofluorocarbons such as CFC 11, CFC 12 and CFC 11 are used.
3, CFC 114, CFC 115, CFC 141b, CFC 225, CFC 124, CFC C-318, CFC 22, CFC 123, CFC 134a, CFC 142
b, Freon 152a, Freon 32, and the like, and liquefied petroleum gas includes propane, iso-butane, n-butane, and the like.

When the propellant is a compressed gas type propellant, the propellant contained in the aerosol container and the form of the drug are as follows. An insoluble gas (such as nitrogen gas) that is compressed and exists in the upper part of the container. Soluble gas (nitrous oxide gas, carbon dioxide gas, etc.) that is compressed and exists in the upper part of the container in a state of being partially dissolved in the stock solution.

As an embodiment other than using the liquefied gas type propellant or the compressed gas type propellant in the aerosol container, a double container is used, and the liquefied gas type or compressed gas type propellant is used as the outer container and the inner container is connected to the valve. There is also a diaphragm system in which a stock solution such as a solution, an ointment, a cream or a paste is filled, and only the stock solution is directly ejected.

The drug is not limited to a drug (active ingredient) alone, but may be a drug to which an auxiliary ingredient is added. The drug is not particularly limited as long as it can be administered rectally or vaginally. For example, a hypnotic sedative, anxiolytic,
Antipyretic and analgesic anti-inflammatory agents, analgesics, anticonvulsants, laxatives, hormonal agents, agents for reproductive organs, antibiotics, hemorrhoids and the like.

Examples of hypnotic sedatives and anxiolytics include chloral hydrate, diazepam, bromazepam, phenobarbital sodium and the like.

Examples of the antipyretic analgesic and anti-inflammatory agent include acetaminophen, aspirin, sulpirine, indomethacin, diclofenac sodium, ibuprofen, buprenorphine hydrochloride, ketoprofen, piroxicam and the like.

Examples of analgesics include morphine or its hydrochloride, pentazocine or its hydrochloride.

Examples of the antispasmodic agent include butylscopolamine bromide and the like.

Examples of laxatives include bisacodyl and a mixture of sodium dihydrogen phosphate and sodium hydrogen carbonate.

Examples of the hormonal agents include gemprost and buserelin acetate.

Examples of agents for reproductive organs are chloramphenicol, tricomycin, pimaricin, estriol,
Animal products such as clotrimazole, isoconazole nitrate, econazole nitrate, oxyconazole nitrate, miconazole nitrate, tinidazole, protein silver, metronidazole, calf blood extract, fradiomycin estriol, carbalzone, benzethonium chloride, diphenhydramine hydrochloride, An example is a crystalline α-chymotrypsin mixture.

Examples of antibiotics include penicillins, cephalosporins, carbapenems and the like.

Examples of hemorrhoidal agents include suspension of killed Escherichia coli, bismuth subnitrate / naphazoline hydrochloride / diphenhydramine / dibucaine hydrochloride / azulene mixture, hydrocortisone caproate / undecylate cremizole / dibucaine / hexachlorophene hydrochloride mixture, tribenocide / lidocaine mixture, E. coli killed bacteria / procaine hydrochloride mixture, valeric acid diflucortron / lidocaine mixture, epidihydrocholesterin / ethyl aminobenzoate / sulfisomidine mixture, hydrocortisone / fradiomycin sulfate /
Dibucaine hydrochloride / escroside mixture, lidocaine / bismuth subgallate / ethyl aminobenzoate / zinc oxide mixture, Escherichia coli killed bacteria suspension / hydrocortisone mixture, shikon extract / ethyl aminobenzoate / dibucaine hydrochloride /
Diphenhydramine hydrochloride / cetrimide mixture, hydrochloric acid 2-
(3,4-dihydroxyphenyl) -tetrahydro-
Examples include 1,4-oxazine / aluminum lactate / bismuth subgallate mixture, funnel extract / tannin mixture and the like.

Further, as other drugs, domperidone, calcitonin derivative and the like are exemplified.

As auxiliary components, stabilizers, surfactants, solubilizers, bases, binders, adsorbents, suspending agents, antioxidants, wetting agents, emulsifiers, thickening agents, foaming agents, excipients, etc. Examples include excipients, dispersants, preservatives, solubilizers, and the like.

As the stabilizer, cocoa butter, light anhydrous silicic acid, crystalline cellulose, sesame oil, zinc oxide, cyclodextrin, sucrose fatty acid ester, stearic acid, magnesium stearate, soybean lecithin, lanolin, vitamin E, glycerin, Examples include propyl gallate polysorbate and macrogol.

As the surfactant, sucrose fatty acid ester, stearyl alcohol, sorbitan fatty acid ester, sorbitan trioleate, polysorbate 60,
Examples thereof include polysorbate 80, macrogol 400, sorbitan monooleate, sorbitan monostearate, sodium lauryl sulfate and the like.

As the solubilizer, HS-12-P, sodium benzoate, isopropanol, ethanol, glycerin, polyoxyl 40 stearate, soybean lecithin, propylene glycol, oleic acid, paraffin,
Examples include Lauro Macrogol, Macrogol 300, Macrogol 4000, and the like.

Examples of the binder include gum arabic, carboxymethyl ethyl cellulose, cellulose, stearyl alcohol, gelatin, hydroxypropyl methyl cellulose, polysorbate 80, olive oil, petrolatum, lanolin, methyl cellulose, sodium carboxymethyl cellulose and the like.

Examples of the suspending agent include gum arabic, carmellose sodium, sorbitan fatty acid ester, polysorbate 80, macrogol 6000, methyl cellulose, sorbitan monolaurate, lecithin and the like.

As the emulsifier, sucrose fatty acid ester,
Examples include purified soybean lecithin, sorbitan fatty acid ester, sorbole, medium chain fatty acid triglyceride, sorbitan trioleate, polysorbate, phospholipid, sodium lauryl sulfate and the like.

[0044]

The present invention will be described more specifically with reference to the following examples. Example 1 In this example, an aerosol preparation for the purpose of antipyretic analgesic and anti-inflammatory treatment, which is capable of injecting a nozzle through an anus and injecting a drug into the rectum, was actually manufactured.

(1) Aerosol container (including valve and actuator part) A cylindrical aluminum monoblock can having an outer diameter of 25 mm and an internal volume of 6 ml was provided with a metering valve with a single injection amount of 100 μl. . The actuator part is shown in FIG.
As schematically shown in FIG. 1, the shape is such that it has a cylindrical body 11 capable of accommodating substantially the entire aerosol container. In the figure, a part of the actuator portion is cut away.
The stem of the metering valve is connected to the innermost portion of the body 1, and the ejected substance is guided to the outside in a direction perpendicular to the longitudinal axis of the aerosol container. The bottom of the container is exposed from the body 11 by an amount capable of pushing the aerosol container 2. A cap may be attached to this portion to prevent accidental pushing. The overall size of the aerosol container including the actuator is 60 mm.
Met.

(2) Nozzle As shown in FIG. 4, the nozzle has a cylindrical shape which can be removably fitted in the actuator section of (1) in an airtight manner. The outer diameter of the body is φ29 mm,
The protrusion length from the side surface of the actuator portion was 65 mm, and the nozzle hole at the tip portion was a straight nozzle type. Further, the mode of the sprayed medicine was set so as to become a mist.

(3) Names and blending ratios of drugs and propellants [Drugs] indomethacin; 10 (wt%), oleic acid; 4 (wt%), soy lecithin; 2 (wt%), sorbitan trioleate; 4 (weight%). [Propellant] Freon 11; 40 (% by weight), Freon 12;
40 (wt%).

By changing only the formulation of the medicine and the specifications of the propellant in the above-mentioned Example 1, aerosol formulations for drug administration to the rectum as shown in Examples 2 to 5 below were produced.

Example 2 In this example, an aerosol preparation for the purpose of antipyretic analgesic and anti-inflammatory was produced in the same manner as in Example 1 above. [Drug] diclofenac sodium; 20 (wt%),
Sorbitan trioleate; 5 (wt%), Macrogol 400; 5 (wt%). [Propellant] Freon 11; 20 (% by weight), Freon 12;
30 (wt%), Freon 134a; 20 (wt%).

Example 3 In this example, an aerosol formulation intended for treating hemorrhoids was produced. [Drug] diflucortron valerate; 0.2 (wt%),
Lidocaine; 40 (wt%), soy lecithin; 4.8
(Wt%), oleic acid; 5 (wt%). [Propellant] Freon 114; 15 (% by weight), Freon 13
4a; 35 (wt%).

Example 4 In this example, an aerosol preparation for treating hemorrhoids was produced in the same manner as in Example 3 above. [Drug] hydrocortisone; 2.5 (wt%), fradiomycin sulfate; 3.55 (wt%), dibucaine hydrochloride; 2.5 (wt%), escroside; 5 (wt%),
Oleic acid; 3.45 (wt%), soybean lecithin; 2
(weight%). [Propellant] Freon 134a; 38 (wt%), Freon 1
1; 30 (% by weight).

Example 5 In this example, an aerosol preparation for the purpose of antipyretic analgesic and anti-inflammatory was produced in the same manner as in Example 1 above. [Drug] piroxicam; 20 (wt%), sorbitan trioleate; 5 (wt%). [Propellant] Freon 134a; 20 (wt%), Freon 1
1; 20 (wt%), Freon 12; 35 (wt%).

When the aerosol preparations produced in the above Examples 1 to 5 were actually applied to the rectum, it was found that they could be easily and hygienically applied to the administration site.

[0054]

INDUSTRIAL APPLICABILITY As described above in detail, the aerosol preparation according to the present invention can make the absorption of a drug from the rectum or vagina or the action of the drug on the rectum or vagina prompt and effective. It is possible. Further, the aerosol preparation according to the present invention can be easily and hygienically applied to these administration sites.

[Brief description of drawings]

FIG. 1 is a cross-sectional view schematically showing a structural example of an aerosol preparation of the present invention.

FIG. 2 is a sectional view schematically showing an example of a general basic structure of a valve.

FIG. 3 is a sectional view schematically showing an example of a basic structure of a metering valve.

FIG. 4 is a cross-sectional view schematically showing an example of the aerosol preparation according to the present invention.

[Explanation of symbols]

 1 Actuator part 2 Valve 3 Aerosol container 4 Chemical 5 Propellant 6 Nozzle

Claims (3)

[Claims] 1. A drug which can be administered to the rectum or vagina in an aerosol container having an actuator part provided with a nozzle having an external shape adapted for insertion into the rectum or vagina and a valve opened and closed by the actuator part. The drug administration to the rectum or vagina is characterized in that a drug containing is enclosed with a propellant, the valve is opened by the operation of the actuator section, and the drug is ejected from a nozzle by the pressure of the propellant. Aerosol formulation for use. 2. The aerosol preparation according to claim 2, wherein the valve is a metered valve. 3. The aerosol preparation according to claim 1, wherein the form of the drug sprayed from the nozzle is in the form of mist, foam or powder.