JP2000053562A - Spraying composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a spraying composition for an aerosol preparation or a spray preparation using a new propellant instead of a fluorocarbon-based propellant. SOLUTION: This spraying composition comprises a physiologically active component, a solvent to dissolve the physiologically active component and a carbon dioxide gas. The physiologically active component is a physiologically active medicine absorbable in vivo by oral administration. Water, an alcohol, or the like, preferable as the solvent. An aerosol preparation packed with the composition secures uniform and quantitative spray of the physiologically active component in spraying.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition for injection used in an aerosol preparation or a spray preparation, and more particularly, to a method for quantitatively and uniformly treating a physiologically active ingredient contained in the composition. It relates to a sprayable pharmaceutical composition.

[0002]

2. Description of the Related Art Conventionally, injection preparations for inhalation (for inhalation), including bronchodilators and bronchoconstriction inhibitors, which are therapeutic agents for respiratory diseases such as bronchial asthma, antiallergic agents, coronary artery dilators, etc. Aerosol preparations or sprays) have been developed. In addition to nasal sprays, nasal spray formulations as nasal sprays have been developed for various drugs such as antiallergic agents.

[0003] Such an aerosol preparation or the like is obtained by pulverizing a physiologically active component into fine powder and filling the fine powder into a container together with a propellant (propellant). In use, the active ingredient is quickly delivered into the absorbing tissue by injecting (spraying) the ingredient filled in the container into the oral cavity or nasal cavity by the propellant injection pressure, and inhaling the active ingredient. It is a formulation that exerts its attention and is attracting attention because of its immediate effect and convenience of carrying.

By the way, as the propellant in the conventional aerosol preparations and the like, mainly a CFC-based gas is used. However, the use of chlorofluorocarbon-based gas as a substance causing global warming or depletion of the ozone layer has been regulated worldwide. Therefore, chlorofluorocarbon-based gas, which can be used for aerosols or sprays, is not used. At present, there is a strong demand for the development of pharmaceutical compositions using new alternative propellants.

[0005]

Accordingly, the present invention provides
In view of the above situation, an object of the present invention is to provide a jetting composition for an aerosol formulation or a spray formulation using a new propellant instead of a CFC-based propellant.

In order to solve such a problem, the present inventors have paid attention to carbon dioxide gas which is medically used as a propellant which can be used for aerosol preparations or sprays. However, when carbon dioxide gas is used as a propellant, the desired jetting ability similar to that of a chlorofluorocarbon-based gas can be ensured, but it is relatively difficult to fill the container with the physiologically active ingredient itself. In addition, even if it is filled, it is not possible to secure a quantitative and uniform injection of the active ingredient at the time of injection, and the active ingredient to be injected gradually decreases due to use over time, and the intended therapeutic effect is reduced. The problem that cannot be mentioned was found.

The inventors of the present invention have conducted further intensive studies in order to solve the problem. As a result, after dissolving the physiologically active ingredient using a solvent capable of dissolving the physiologically active ingredient, the present invention was filled together with carbon dioxide into a container. Then, it was found that the physiologically active ingredient can be easily filled, and furthermore, the physiologically active ingredient thus filled can be uniformly and quantitatively sprayed, thereby completing the present invention. .

[0008]

Accordingly, the present invention provides, as one aspect thereof, a jetting composition comprising a physiologically active component, a solvent for dissolving the physiologically active component, and carbon dioxide.

In another aspect, the present invention provides a method of injecting a physiologically active ingredient in place of a CFC-based propellant. Provided is a method for quantitatively injecting a physiologically active ingredient encapsulated in a liquid.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention particularly uses carbon dioxide as a propellant for aerosol preparations or spray preparations, and is characterized in that a physiologically active ingredient to be filled together with carbon dioxide is dissolved in a solvent and used. There are features.

According to the study of the present inventors, even if a carbon dioxide gas is simply used as a propellant to form an aerosol formulation, the physiologically active ingredient filled together with the carbon dioxide gas cannot be uniformly injected. However, surprisingly, when dissolved and used in a solvent capable of dissolving a physiologically active ingredient, it is quite specific in that a desired quantitative and uniform injection can be performed. Furthermore, in view of the fact that aerosol preparations using only carbon dioxide as a propellant and spray preparations did not exist, the propellant composition provided by the present invention can be said to be completely novel. .

According to the study of the present inventors, the physiologically active ingredient that can be filled in an aerosol formulation using a jet composition based on such a specific combination is particularly limited to only a specific drug. However, it has been found that any drug can be applied as long as it is a bioactive drug that can be absorbed in vivo by oral administration.

[0013] Examples of such a bioactive drug capable of being absorbed in vivo by oral administration include a sedative-hypnotic, an antiepileptic, a minor tranquilizer, a major tranquilizer, an antidepressant, a muscle relaxant, Allergic agents, antirheumatic agents, inotropic agents, antiarrhythmic agents, diuretic hypotensive agents, α-blockers, β-blockers, calcium antagonists, angiotensin conversion inhibitors (ACE inhibitors), antihypertensives, vitamins, coronary vessels Dilators, cerebral circulation metabolism improvers, anti-atherosclerotic agents, cardiovascular agents, bronchodilators, anti-asthmatic agents, immunosuppressants, anti-ulcer agents, antiemetic agents, obesity treatments,
Platelet aggregation inhibitors, agents for treating diabetes / diabetes complications, corticosteroids, DNA / RNA drugs, etc., among which bronchodilators, bronchoconstriction inhibitors, corticosteroids, anti-asthmatic agents, immunosuppression Drugs which have already been developed as aerosol formulations or spray formulations in medical applications, such as agents and coronary vasodilators, are particularly preferred.

Further, examples of other physiologically active ingredients include cosmetic ingredients such as a hair restorer, a hair restorer, an antiperspirant and a deodorant.

The above-mentioned physiologically active drugs may be used in clinical trials in addition to those already used and already used in medical practice. Examples of such a drug include those having the following general names. It goes without saying that the following examples are not intended to limit the invention.

Hypnotic sedatives include lormetazepam, quazepam, sorbidem and the like; antiepileptic agents such as sodium valproate and sabril; minor tranquilizers such as diazepam, buspirone, and suriclone; major tranquilizers include cerretide diethylamine; Emonapride, risperidone, mosapramine hydrochloride, etc .; as antidepressants, trazoton hydrochloride, fluvoxamine, dimerdin, rolipram, etc .; as muscle relaxants,
Pinaverium, inaperizone hydrochloride, simeropium bromide,
Cimetropium bromide and the like; anti-allergic or anti-asthmatic agents such as pemirolast potassium, tazanolast, traxanox sodium, dolkast, emedastine fumarate, rotatadine, seritidine, suplatast tosilate, celabenast, bateplast, doquarast, butenafine hydrochloride, pentyfin Jetide, bicumasulo, levocabastine and the like; examples of antirheumatic agents include salazosulfapyridine, nucleomedone, platonin, actarit and the like.

In addition, as cardiotonic agents, xamoterol,
Vesnarinone, nitroprusside, amrinone, xamoterol, docarpamine, isosorbide dinitrate, ibopamine, enoximone, loprinone, fenoldopane, pimobendan, milrinone, etc .; as antiarrhythmic agents, flecainide acetate, pirdicinide hydrochloride, cibenzoline succinate, beprilone punch, somiamide hydrochloride Pirmenol hydrochloride, molacidin and the like.

Further, diuretic antihypertensives include α-hump, torasemide and the like; α-blockers such as doxazosin mesylate, tamsulosin hydrochloride, bunazosin hydrochloride and the like; β-blockers such as carvedilol, bisoprolol fumarate and litisolol. Xybenolol hydrochloride, ceriprolol hydrochloride, metoprolol tartrate, carteolol hydrochloride, bopindolol malonate, betaxolol hydrochloride, bevantolol hydrochloride, etc .; as calcium antagonists, bepridil hydrochloride, nisoldipine, nimodipine,
Nitrendipine, flomethidine, nakadipine, galopamil, manidipine hydrochloride, paronidipine, nitrendipine,
Examples include mepiradipine hydrochloride, fasudil hydrochloride, silnidipine, sesamodyl fumarate, amlodipine besylate, efonidipine hydrochloride, diltiazem hydrochloride, clentiazem maleate, lacidipine, focidipine, felodipine, nilvadipine, remacarim, asanidipine, pranidipine, isradipine and the like.

Further, examples of angiotensin conversion inhibitors (ACE inhibitors) include althiopril calcium, cilazapril, ramipril, lisinopril, temocapril, spirapril, imidapril hydrochloride, benasepril, quinapril, fosenopril and the like;
Tartaric ketanserin, pinacidil, diazoxide, naftopidil, clonidine, Furokisenan, chroma potassium; cyanocobalamin as various vitamins, methyl cyanocobalamin, mecobalamin, and vitamin B ₁₂ derivatives such as hydroxocobalamin.

Examples of coronary vasodilators include isosorbide, molsidomine and the like; agents for improving cerebral circulation and metabolism include ademethionine tosylate sulfate, dihydroergotoxine mesylate,
Aniracetam, naftidrofuryl oxalate, teniloxazine maleate, minabrin hydrochloride, buflomedil hydrochloride,
Oxiracetam, azetilerin, vinconede, erythritol, fasudil hydrochloride, amylizine hydrochloride, tamoraridin, nebracetam fumarate, ergiverine, etc .; as anti-atherosclerotic agents, bezafibrate, cholestyramine,
Boliceride, simvastatin, etc .;
Levocarnitine chloride, alinidine hydrobromide and the like; Examples of bronchodilators include oxitropium bromide, theophylline, ozacrel hydrochloride, salmeterol, tulopterol hydrochloride and the like.

[0021] Anti-ulcer agents include proamipide,
Misoprostol, nizatidine, enprostil, albaprostil, lotraxate hydrochloride, embrostil,
Trimoprostil, rotraxate hydrochloride, omeprazole, beperidium iodide, lansoprazole, lyoprostil, polaprezinc, reminoprazole, mezolidone, nocloprost, acetoxolone, etc .; Cisapride and the like; obesity therapeutic agents as mazindol; platelet aggregation inhibitors as tedelparin, argipidine, airoprost, ataprost, beraprost potassium, carbacycline, isvocrel, sarpogrelate hydrochloride, satigrel, clopidocrel and the like.

Examples of the therapeutic agent for diabetes and diabetic complications include pioglidazone hydrochloride, voctibose, gliclazide, acarbose, cyglitazone, soorvinyl, gumpiride, epalrestat, ganglioside, midaglizole hydrochloride, ponarestat and the like; Triamcinolone, dexamethasone, flunisolide, velcometasone, beclomethasone propionate, fluorometholone, hydrocortisone succinate, paramethasone acetate, betamethasone, cortisone, fluticasone propionate, etc .; cyclosporine as an immunosuppressant; DNA / RN
Drug A includes transgene RNA in genetic therapy,
DNA, antisense and the like can be mentioned.

On the other hand, the solvent used for dissolving the above-mentioned various physiologically active drugs and used together with the carbon dioxide gas is one which can dissolve the physiologically active drug, and has a pharmacological effect upon injection into the oral cavity or the nasal cavity. There is no particular limitation as long as safety is ensured, for example, water, a fat-based solvent,
Examples thereof include a wax solvent, a hydrocarbon solvent, a fatty acid solvent, an alcohol solvent, an ester solvent or a surfactant solvent, and a mixture of a plurality of these solvents.

Specific examples of such fats and oils solvents include:
Vegetable oils such as olive oil, sesame oil, safflower oil and soybean oil; waxes such as beeswax and liquid lanolin; waxes such as liquid paraffin, squalane and petrolatum; Examples thereof include lower fatty acids such as acetic acid and lactic acid, and higher fatty acids such as oleic acid and isostearic acid.

Examples of the alcohol solvent include lower alcohols such as ethanol, propanol and isopropanol; polyhydric alcohols such as ethylene glycol, ethylene glycol monoalkyl ether, polyethylene glycol, propylene glycol, butylene glycol and glycerin; ester solvents. As, diisopropyl adipate, hexyldecyl isostearate,
Ester solvents such as oleyl oleate, butyl stearate, diisopropyl sebacate, diethyl phthalate, octyldodecyl myristate, myristyl myristate, and hexyl laurate are mentioned.

Further, the surfactant includes various anionic, cationic and amphoteric surfactants capable of dissolving a desired physiologically active drug. Among these solvents, water, liquid paraffin, ethanol, isopropyl adipate,
Solvents such as propylene glycol and oleic acid are preferred, with ethanol being particularly preferred.

On the other hand, as the propellant, that is, carbon dioxide gas as a propellant, liquefied carbon dioxide gas which is medically used is preferably used. Therefore, the composition for injection provided by the present invention is a composition that can be used for an aerosol or a spray, in view of using carbon dioxide as a propellant, and a cylinder-type container for the composition. Things are used.

The preparation of the composition for injection provided by the present invention comprises the steps of:
It depends on the amount of a single injection of the physiologically active ingredient to be filled and used in the above-mentioned cylinder, and the expected number of uses. In other words, the amount of the physiologically active ingredient to be filled is determined by the amount of the physiologically active ingredient that can provide a desired therapeutic effect by one injection and the desired number of injections (the number of inhalations), and the solvent that dissolves the amount is determined. The amount as well as the amount of carbon dioxide that can be injected will be determined and adjusted.

Specifically, although the type of the physiologically active ingredient cannot be generally limited, the amount determined above is slightly excessive, preferably 1.2 to 5 times the amount, more preferably 1. One to three times the amount of the physiologically active ingredient dissolved in a solvent capable of dissolving is put in the container. Next, a slightly excessive amount of carbon dioxide gas in an amount capable of performing the desired number of injections, preferably 1.1 to 3 times, more preferably 1.
By filling the container with 1-2 times the amount of carbon dioxide,
An aerosol formulation using the composition of the present invention can be prepared. In this case, if the gas pressure is within the range where the liquefied carbon dioxide gas is present, it is sufficient from the viewpoint of safety and the like.

In the aerosol preparation using the composition of the present invention prepared as described above, the effective therapeutic amount of the physiologically active ingredient contained in one injection is quantitatively and uniformly injected. No decrease in the injection amount was observed even after use over time.

[0031]

The present invention will be described below in more detail with reference to examples, comparative examples and various test examples.

Example 1 As a physiologically active drug, beclomethasone propionate, which is an adrenocortical hormone and used for bronchial asthma, was selected, and an aerosol preparation was prepared by the following method. 13. Double the amount of normal composition.
3. A solution prepared by dissolving 6 mg (100 μg / time as an expected injection amount) of beclomethasone propionate in 800 μl of ethanol was placed in a spray cylinder, and carbon dioxide was sprayed from the spray cylinder (filled with carbon dioxide gas) using an injection device. An aerosol formulation was prepared by filling 45 g.

Example 2: In the same manner as in Example 1 described above, 14.6 mg which is twice the amount of the usual composition (1
00 μg / time) beclomethasone propionate for 800
The solution dissolved in μl of ethanol was placed in a spray cylinder, and 7.35 g of carbon dioxide was charged from the spray cylinder (filled with carbon dioxide) using an injection device to prepare an aerosol formulation.

Injection Quantitative Test Using the aerosol preparations prepared in Examples 1 and 2 above, injection was performed as a set of 10 injections, and the weight of the carbon dioxide gas injected in one set and the physiologically active ingredient were measured. HPLC for beclomethasone propionate
Was determined.

Test 1: 11 sets of aerosol preparations prepared according to Example 1 (110 injections)
The amount of carbon dioxide gas injected in each set and the amount of beclomethasone propionate injected in each set were quantified for 1 to 8 sets. The result is shown in FIG.

Test 2: 12 sets of aerosol preparations prepared in Example 2 (120 injections)
The amount of carbon dioxide gas injected in each set and the amount of beclomethasone propionate injected in each set were quantified for 1 to 7 and 10 sets. The result is shown in FIG.

As is clear from the results shown in FIGS. 1 and 2, the amount of the physiologically active component injected by each injection number does not decrease, and uniform quantitative injection is performed. It is understood that.

Comparative Example: An aerosol preparation was prepared by filling only with carbon dioxide using beclomethasone propionate, which is the same physiologically active ingredient as in Examples 1 and 2.
That is, a spray cylinder (filled with carbon dioxide gas) is 14.6 mg (double as the normal composition amount) (1
(00 μg / time) beclomethasone propionate was charged into an empty spray cylinder together with 4.5 g of carbon dioxide using an injection jig to prepare an aerosol formulation.

Injection Quantitative Test Using the aerosol preparation prepared according to the above comparative example, injection was performed with 10 injections as one set, and the weight of the carbon dioxide gas injected in each set and beclomethasone propionate, a physiologically active ingredient, were injected. Was quantified by HPLC. That is, 18 sets (180 injections) were performed, and the weight of carbon dioxide gas injected in each set and
For each set of 1, 3, 5, and 7, the amount of beclomethasone propionate injected was quantified. The result is shown in FIG.

As can be seen from the results shown in the figure, the aerosol preparation of the comparative example is insufficiently filled with the physiologically active ingredient, and the amount of the physiologically active ingredient injected at each injection frequency is not limited. Is reduced, and it is found that uniform quantitative injection is not performed. Therefore, the desired therapeutic effect cannot be obtained with this aerosol preparation, and the usefulness of the composition of the present invention is understood.

Stability test: (1) Confirmation test of impurities in cylinder: A sample in which only a carbon dioxide gas was filled in a 3.4 L cylinder was prepared, and immediately after the preparation, one month and three months later, impurities in the cylinder were measured. The presence or absence of was confirmed by gas chromatography and HPLC. As a result, immediately after preparation,
Even after one month and three months, generation of impurities and the like was not observed in the cylinder, and stability when carbon dioxide was used as a propellant (propellant) was confirmed.

(2) Long-term stability test The stability test of a physiologically active ingredient under long-term storage conditions when a physiologically active ingredient was dissolved in a solvent and filled with carbon dioxide gas in a spray cylinder was performed using the following samples. I went to the target. That is, a sample in which only a carbon dioxide gas was filled in a 3.4-liter cylinder as a control, and a sample in which beclomethasone propionate was used as a physiologically active ingredient as a test sample, which was dissolved in oleic acid as a solvent, and filled with carbon dioxide gas Was prepared.

For both samples, immediately after filling,
As a long-term stability test by preserving the contents after 3 months and 3 months, the presence or absence of impurity generation in each cylinder and the presence or absence of denaturation of beclomethasone propionate in the test sample were measured by HPLC.

As a result, generation of impurities in the cylinder was not recognized as a change with time in both samples. Also, no denaturation of beclomethasone propionate was observed in the test sample, and it was confirmed that the stability was good. In addition, although the test using ethanol as a solvent was performed similarly, the same safety was confirmed also in this case.

The same applies to drugs other than beclomethasone propionate as a physiologically active ingredient. In addition, the present invention can also be applied to cosmetics other than physiologically active drugs as physiologically active ingredients, for example, hair cosmetics such as hair restorer and hair restorer, deodorant products such as antiperspirant sprays, foot care products, and the like. It should be noted that the physiologically active component also includes components applicable to these.

[0046]

As described above, the present invention provides a composition for injection and inhalation using carbon dioxide gas as a new propellant in place of the conventional chlorofluorocarbon-based gas, and is contained in the composition. When used together with a solvent that dissolves a physiologically active ingredient, it is completely specific in that a desired physiologically active ingredient can be quantitatively and uniformly sprayed. Therefore, it can be said that this is extremely valuable in that it can provide an aerosol formulation or a spray using a new propellant in place of Freon gas whose use will be regulated in the future.

[Brief description of the drawings]

FIG. 1 is a view showing the results of a jet quantitative test for the preparation of Example 1.

FIG. 2 is a graph showing the results of a jet quantitative test for the preparation of Example 2.

FIG. 3 is a view showing the results of a jet quantitative test on a preparation of a comparative example.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Yuji Morimoto 317-1 Villeforet Inage, 37-1 Naganumaharamachi, Inage-ku, Chiba-shi, Chiba Prefecture (72) Inventor Takaki Nishimoto 5-377 Inage-cho, Inage-ku, Chiba-shi, Chiba −18 Green Palace 202 No.F term (reference) 4C076 AA24 AA93 BB01 CC01 CC03 CC04 CC07 CC11 CC12 CC13 CC14 CC15 CC16 CC17 CC21 CC22 CC30 DD02E DD12E DD16E DD29 DD34E DD37E DD38E DD41E DD43E DD45E DD47E EE23E EE53E67E55E

Claims (10)

[Claims] An injection composition comprising a physiologically active ingredient, a solvent for dissolving the physiologically active ingredient, and carbon dioxide. 2. The injection composition according to claim 1, wherein the physiologically active ingredient is a physiologically active drug capable of being absorbed in a living body by oral administration. 3. A physiologically active drug which can be absorbed in vivo by oral administration is a hypnotic sedative, an anti-epileptic agent, a minor tranquilizer, a major tranquilizer, an antidepressant, a muscle relaxant, an antiallergic agent, an antirheumatic agent, Cardiotonic, antiarrhythmic, diuretic hypotensive, α-blocker, β-blocker, calcium antagonist, angiotensin conversion inhibitor (ACE inhibitor), antihypertensive, vitamin, coronary vasodilator, cerebral circulation metabolism improvement Agents, anti-atherosclerotic agents, cardiovascular agents, bronchodilators, anti-asthmatic agents, immunosuppressants, anti-ulcer agents, antiemetic agents, antiobesity agents, platelet aggregation inhibitors, antidiabetic / diabetic complications, corticosteroids The composition for injection according to claim 1 or 2, which is a DNA / RNA drug. 4. The solvent for dissolving the physiologically active component is water, an oil-based solvent, a wax-based solvent, a hydrocarbon-based solvent, a fatty acid-based solvent, an alcohol-based solvent, an ester-based solvent, or a surfactant-based solvent. The composition for injection according to claim 1, which is a mixture of a plurality of solvents. 5. Hypnotic sedatives, antiepileptics, minor tranquilizers, major tranquilizers, antidepressants, muscle relaxants, antiallergic agents, antirheumatic agents, inotropic agents, antiarrhythmic agents, diuretic hypotensive agents, α-blocker agents , Β-blockers, calcium antagonists, angiotensin conversion inhibitors (ACE inhibitors), antihypertensives, vitamins, coronary vasodilators, cerebral circulation metabolism improvers, anti-atherosclerotic agents, cardiovascular agents, bronchodilators, In vivo absorption by oral administration selected from anti-asthmatic, immunosuppressant, anti-ulcer, antiemetic, obesity, platelet aggregation inhibitor, diabetic / diabetic complications, adrenocortical hormone and DNA / RNA drugs Physiologically active component capable of water solubility; water, oil and fat solvent, wax solvent, hydrocarbon solvent, fatty acid solvent, alcohol solvent, ester solvent or surfactant Solvent, and a solvent for dissolving the physiologically active ingredient selected from the plurality of mixed solvent; and, injecting a composition comprising carbon dioxide gas. 6. The composition for injection according to claim 1, which is used as an aerosol preparation or a spray preparation. 7. A quantitative injection method of a physiologically active ingredient, comprising dissolving a physiologically active ingredient in a solvent and enclosing the same with carbon dioxide in a container. 8. The injection method according to claim 7, wherein the bioactive component is a bioactive drug capable of being absorbed in a living body by oral administration. 9. A bioactive drug capable of being absorbed in vivo by oral administration is a hypnotic sedative, an antiepileptic agent, a minor tranquilizer, a major tranquilizer, an antidepressant, a muscle relaxant, an antiallergic agent, an antirheumatic agent, Cardiotonic, antiarrhythmic, diuretic hypotensive, α-blocker, β-blocker, calcium antagonist, angiotensin conversion inhibitor (ACE inhibitor), antihypertensive, vitamin, coronary vasodilator, cerebral circulation metabolism improvement Agents, anti-atherosclerotic agents, cardiovascular agents, bronchodilators, anti-asthmatic agents, immunosuppressants, anti-ulcer agents, antiemetic agents, antiobesity agents, platelet aggregation inhibitors, antidiabetic / diabetic complications, corticosteroids The injection method according to claim 7, which is a DNA / RNA drug. 10. The solvent for dissolving a physiologically active ingredient is water,
The injection method according to claim 7, which is an oil-based solvent, a wax-based solvent, a hydrocarbon-based solvent, a fatty acid-based solvent, an alcohol-based solvent, an ester-based solvent, a surfactant-based solvent, or a mixed solvent of a plurality of these.