JP2001002589A - Composition for nasal administration enabling mild raising of medicine blood concentration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition enabling high absorption without causing rapid increase of medicine blood concentration in order to avoid adverse effect due to rapid increase of medicine blood concentration after administration of medicine by including a medicine and a hydrogel forming base. SOLUTION: This composition comprises (A) a medicine and (B) a hydrogel- forming base. The component A includes preferably a non-peptide, a proteinous medicine (e.g. antiphlogistic steroidal medicine, analgesic antiphlogistic medicine, antitussive expectorant, antihistamic medicine, antiallergic medicine, bronchodilator, antiemetic medicine, medicine for migraine, sleep inducing medicine, sleep sedative or vitamin) or a peptide-proteinous medicine having <=30,000 molecular weight and the component B includes e.g. lower alkyl ether of cellulose, acrylic starch, crospovidone, carboxyvinyl polymer, polyvinyl alcohol, aminoalkylmethacrylate copolymer or methacrylic acid copolymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition for nasal administration which enables high absorption and a moderate increase in the blood concentration of a drug. More particularly, the present invention relates to a powdery composition for nasal administration comprising a drug and a hydrogel-forming particulate base having a suitable interaction with the drug.

[0002] The present invention provides a method for treating a patient who requires a therapeutically desirable drug whose blood concentration is moderate rather than abruptly increased after administration by a doctor, a nurse, the patient, etc. To provide a composition for nasal administration to be administered to

[0003]

2. Description of the Related Art Nasal administration is one of the useful methods from the viewpoints of compliance, efficacy, and the like for drugs that are taken for a long period of time and are difficult to administer orally. WO97 / 31626 describes a technique for increasing the absorption of a drug for a composition powder for nasal administration. This technique primarily achieves an increase in overall absorption by increasing the initial drug blood concentration. Therefore, the blood concentration of the drug is expected to increase rapidly from 0 immediately after administration, and there is a possibility that side effects may occur depending on the drug. Japanese Patent Publication No. 60-34925 discloses a technique for sustaining a drug concentration in the blood of a composition for nasal administration. In the composition powder for nasal administration, a mucoadhesive base is used to delay the clearance of the drug to the pharynx, thereby improving the retention of the drug, thereby improving the absorption rate. However, since the base becomes a viscous liquid after absorbing water, the drug concentration in the blood is maintained at a low concentration as compared with the above-mentioned technique. Therefore, although the absorption rate is improved as compared with the aqueous solution, some drugs may not reach the effective blood concentration.

[0004]

It is known that many drugs have side effects due to an increase in drug blood concentration. The side effects include those with relatively little hindrance such as drowsiness, and serious ones, such as cardiac arrest and dyspnea, may lead to death of the patient. To give an example in the latter,
Ventricular and atrial fibrillation and cardiac arrest by antiarrhythmic drugs quinidine, propafenone, cibenzoline and pirdicanide, blood pressure reduction by angina pectoris nitroglycerin and atrioventricular block by diltiazem, vasodilators PGE ₁ and lipo PGE ₁ Shock, antihypertensive drug diltiazem hydrochloride,
Examples include complete atrioventricular block by nipradilol, dyspnea and cardiac arrest by epinephrine as a vasopressor, impaired consciousness and shock due to theophylline as a bronchodilator.

[0005] Further, it is known that some drugs have a narrow safety range in which the effective blood concentration and the concentration at which side effects occur are extremely close to each other. For example, digoxin, a cardiotonic drug, warfarin, an antithrombotic drug, phenytoin, an antiepileptic drug, barbital, pentobarbital salt, and secobarbital salt, which are sleep sedatives, are known.

[0006] In the case of a drug having the above-mentioned properties, a sudden increase in blood concentration immediately after administration may cause side effects and is not suitable. As an example, the calcium antagonist nisoldipine has side effects due to acute vasodilation associated with a rapid increase in blood concentration, but it can be avoided by maintaining the formulation, American Journal o.
f Cardiology, 75, 46E-53E, 1995. In addition, even if the concentration exceeds the level at which side effects occur, healthcare workers will have time to deal with the side effects,
It is safer to have a moderate rise in blood levels. Depending on the disease, a preparation whose blood concentration gradually decreases after reaching the effective blood concentration may be desirable for the therapeutic effect. It is common for nasal preparations to take a blood pattern in which the maximum blood concentration is reached shortly after administration and the blood concentration of the drug rapidly decreases thereafter. However, some drugs are not suitable for use because of the side effects mentioned above. In addition, in the case of improving the absorption rate of the nasal agent by devising a formulation, the maximum blood concentration and the BA (Bioavailability) are increased while maintaining the above blood pattern. Although many have the advantage of lower doses, the risk of developing side effects is comparable.

[0007] The problems in the prior art described above,
And in view of the problem, as a result of intensive studies by the present inventors,
Nasal administration compositions have been found that do not cause a sudden increase in drug blood concentration while allowing higher absorption than conventional techniques. That is, the present invention is a powdery composition for nasal administration comprising a drug and a hydrogel-forming base, and this composition can be more easily administered to a patient than injection, and can be physically administered. Was also found to be a stable composition.

[0008] The object of the present invention is to provide a composition for nasal administration, which does not cause a sudden increase in drug blood concentration and has high absorption, in order to avoid the above-mentioned side effects.

[0009]

That is, the present invention provides a powdery composition for nasal administration comprising a drug and a hydrogel-forming base.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The drug of the present invention is not particularly limited. For example, non-peptide / protein drugs can be used. Examples include anti-inflammatory steroids, analgesic anti-inflammatory drugs,
Antitussive expectorants, antihistamines, antiallergic drugs, bronchodilators, antiemetics, migraines, sleep-inducing drugs, sleep sedatives,
Vitamins, sex steroid hormones, antitumor drugs, antiarrhythmic / hypertensive drugs, vasopressors, angina pectoris, vasodilators, antithrombotics, antianxiety / psychotropic drugs, antiepileptics, antiulcer drugs, inotropic Drugs, analgesics, peptide / protein drugs and the like can be mentioned. For example, hydrocortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, fluticasone, mometasone, fluocortin, budesonide, salbutamol, antiinflammatory steroids such as salmeterol, acetaminophen, phenacetin, aspirin, aminopyrine, aminopyrine, sulpyrine, phenylbutazone, mefenam Analgesic and anti-inflammatory drugs such as flufenamic acid, ibufenac, ibuprofen, alclofenac, diclofenac, indomethacin, antitussive expectorants such as sodium cromoglycate, codeine phosphate, isoproterenol hydrochloride, diphenhydramine, triprolidine, isotipendil, chlorpheniramine, etc. Antihistamines, Amlexanox, Azelastine, Ozacrel, Tranilus , Antiallergic drugs such as ketotifen, bronchodilators such as theophylline, antiemetic drugs such as ondansetron, granisetron, metoclopramide, cisapride, domperidone, migraine drugs such as butorphanol, sumatriptan, arniditan, and hypnotics such as brotizolam , Sedatives such as barbital, pentobarbital salts, secobarbital salts, etc., vitamins such as cyanocobalamin, mecobalamin, sex steroid hormones such as estradiol, estriol, progesterone, testosterone, antitumor drugs such as tamoxifen, tegafur, quinidine, Elevation of antiarrhythmic / hypertensive drugs such as propafenone, cibenzoline, pirdicanide, diltiazem hydrochloride, nipradilol, propranolol, atenolol, nicardipine, epinephrine, etc. Medicine, nitroglycerin, angina drugs such as diltiazem, antithrombotic drugs such as warfarin, diazepam, an anti-anxiety-psychotropic drugs such as nitrazepam, anti-epileptic drugs such as phenytoin,
Antiulcer drugs such as cimetidine and ranitidine; cardiotonic drugs such as digoxin and dopamine; and analgesics such as buprenorphine.

[0011] Peptide / protein drugs can also be used. Examples thereof include peptide / protein drugs having a molecular weight of 30,000 or less. For more information,
For example, luteinizing hormone releasing hormones, growth hormone releasing factors, somatostatin derivatives, vasopressins, oxytocins, hirudin derivatives, enkephalins, adrenocorticotropic hormone derivatives, bradykinin derivatives, calcitonins, insulins, glucagon derivatives , Growth hormones, growth hormone releasing hormones, luteinizing hormones, insulin-like growth factors,
Calcitonin gene-related peptides, atrial natriuretic peptide derivatives, interferons, erythropoietin, granulocyte colony stimulating factor, macrophage formation stimulating factor, parathyroid hormones, parathyroid hormone releasing hormone, prolactin, thyroid stimulating hormone releasing hormone, Angiotensin, prostaglandins and the like.

The gel-forming base in the present invention means a base in a dry state when immersed in water or another solvent.
It absorbs them and swells. Of these, the base that absorbs water is particularly called a hydrogel, and the amount of water absorbed by the base is called the water content. After sufficient time, the base will no longer absorb water, and the water content at this point is called the equilibrium water content. The value of the water content varies depending on the type of the base, the pH of the aqueous solution to be immersed, the type of the electrolyte, the ionic strength, and the like. In general, a gel having a high water content is soft, and some bases are crushed by their own weight, and cannot maintain the shape of the original base and become a fluid slurry having a high viscosity. However, depending on the base, croscarmellose sodium (AcDiSo
There is also a material such as (l: registered trademark), which has a very high water content of 500% and maintains the original particle shape while swelling.

Among the hydrogel-forming bases, there are those which form a gel without dissolving even after elapse of infinite time, and those which form a gel initially but dissolve after elapse of infinite time. In the latter case, non-dissolvability is achieved by chemically cross-linking by adding a cross-linking agent, or by forming a physical cross-link by increasing the ratio of hydrophobic groups or adding a molecule having a charge opposite to that of the base. Can be used as a base.

The hydrogel-forming base may be a base having sufficient strength to retain its shape as particles even after absorbing water and reaching equilibrium, or water while remaining in the nasal cavity. It is a particulate base material having sufficient strength to retain its shape as particles even when absorbed.

Further, the hydrogel-forming base may be van
der Waals force, hydrogen bonding, hydrophobic interaction, electrostatic action, formation of charge transfer complex, capillary condensation, or physical adsorption of the drug by other factors, the adsorption constant Kp in physiological saline is 5-400mL / g It is preferred that

The hydrogel-forming base of the present invention includes hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium hydroxypropylmethylcellulose, methylcellulose sodium, sodium hydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose calcium, methylcellulose calcium. , Hydroxyethylcellulose calcium, and carboxymethylcellulose calcium. Moreover, what crosslinked the said base material, for example, croscarmellose sodium, etc. can also be used.

In the composition for nasal administration of the present invention, it is preferable that the particle size of the drug is 150 μm or less, since the drug is efficiently deposited in the nasal cavity after administration, and particularly, by pulverization, freeze-drying or spray drying. , The average particle size is 1 to 10
0 μm, or even 1-20 μm, is preferred as higher nasal absorption of the drug is achieved.

Further, in the composition for nasal administration of the present invention,
It is preferred that the drug be dispersed on the surface of the hydrogel-forming base, since higher nasal absorption of the drug over a longer period of time is achieved. As a technique for achieving this, there is a technique in which a hydrogel-forming base is sized to an average particle diameter of 10 to 250 μm and then mechanically mixed with a drug.

Here, the mechanical mixing in the production of the composition of the present invention includes, for example, a V-type mixer which is a rotary type mixer, a cross rotary mixer, a double cone type mixer and the like, and a container. In addition to fixed mixers, such as universal mixers, ribbon mixers, automatic mortars, ball mills, and other mixers, such as high-speed mixers and power-full auto mixers, there is also manual mixing with a mortar.

The amount of the drug used in the present invention is an effective therapeutic amount and can be determined according to each drug, the type and degree of the disease, the age and weight of the patient, and the like. Normally, the amount of each drug is the same as that used for injection.
The amount is 0 times, more preferably the same to 10 times.

The sum of the amount of the drug of the composition of the present invention and the amount of the hydrogel-forming base depends on the therapeutic amount of the drug because the amount of powder applicable to the nasal cavity is limited. The amount is preferably not less than 1 part by weight, particularly preferably not less than 5 parts by weight, more preferably not less than 10 parts by weight, based on 1 part by weight of the drug.

The composition of the present invention may contain, if necessary, known lubricants, binders, diluents, coloring agents, and preservatives in order to improve the physical properties, appearance, and odor of the composition. A preservative, a preservative, a deodorant and the like may be added. As the lubricant, for example, magnesium stearate, stearic acid,
Talc, etc .; binders, for example, starch, dextrin, etc .; diluents, for example, starch, lactose, etc .; coloring agents, for example, Red No. 2, etc .; preservatives, for example, ascorbic acid; Preservatives include, for example, paraoxybenzoic acid esters; and odorants include, for example, menthol.

Also, the composition of the present invention is in a suitable dosage form to be administered as a pharmaceutical. Such forms include capsules filled with the present invention in dosage units, which are sprayed intranasally with a suitable dosage device. In addition, the dosage unit amount of the composition of the present invention or a plurality of dosage unit amounts of the composition of the present invention is housed in an appropriate container, and the dosage unit amount of the composition of the present invention is administered in a single dose during the administration operation. Alternatively, they may be administered in divided doses.

[0024]

EXAMPLES The present invention will be described below with reference to examples.

The adsorption constant Kp described herein is a simplest one of the equilibrium adsorption formulas expressed by W = Kp × C, where W is the amount of adsorption per unit weight of adsorbent (base), C Indicates the concentration of the adsorbate (drug) in the solution.

In the following examples, carboxymethylcellulose calcium may be referred to as CMC-Ca, carboxymethylcellulose as CMC, and microcrystalline cellulose as MCC.

Example 1-3 To 100 mg of a base, 3 mL of a physiological saline solution of carboxyfluorescein or propranolol hydrochloride was added and stirred. After 24 hours, the base was centrifuged, and the concentration of the supernatant was measured. Based on this, the adsorption constant Kp was calculated in physiological saline. Table 1 shows the results.

[0028]

【table 1】

Example 1 was a powder of AcDiSol (registered trademark: manufactured by SMC) of carboxyfluorescein, and Example 2 was a powder of CMC-Ca of carboxyfluorescein. Example 3
A CMC powder of propranolol hydrochloride was prepared. At this time, the base used was classified into 25-63 μm, and the mixing ratio of the main drug model and the base was 1: 100 for carboxyfluorescein and 1: 5 for propranolol hydrochloride in a mortar. 15 mg of each of these compositions was administered to the nasal cavity of a white native male rabbit (body weight: 2.5 to 3.0 kg) using a powder administration device (manufactured by Teijin Limited: Publyzer). After a certain period of time, blood was collected from the ear vein, and the blood concentration of the active drug model was measured by a fluorescence detector of HPLC. Based on the measurement results, the results of converting the dose of the active drug model to 100 mg are shown in FIGS. 1 and 2 for Examples 1 and 2 and FIG. 2 for Example 3. The maximum blood concentration was observed between 30 and 45 minutes. From the above results, it was confirmed that the composition of the present invention enables high absorption and moderate increase in drug blood concentration.

Comparative Example 1 To 100 mg of a base, 3 mL of a carboxyfluorescein physiological saline solution was added, and the mixture was stirred.
After time, the concentration of the supernatant from which the base was centrifuged was measured.
Based on this, the adsorption constant Kp was calculated in physiological saline.
Table 2 shows the results.

[0031]

[Table 2]

In Comparative Example 1, a powder composition was prepared using CMC (Nichirin) as a base and carboxyfluorescein as a principal drug model. At this time, the base was classified into 25-63 μm, and carboxyfluorescein and the base were mixed in a mortar at a mixing ratio of 1: 100. 15 mg of these compositions were used as white native male rabbits (body weight 2.5-3.0).
kg) into the nasal cavity with a powder administration device (manufactured by Teijin Limited: publisher). After a certain period of time, blood was collected from the ear vein, and the blood concentration of the active drug model was measured by a fluorescence detector of HPLC.

Based on the measurement results, the dose of the active drug model was determined.
The result converted to 100 mg is shown in FIG. From the above results, although a base having an adsorption constant Kp exceeding the range of 5-400 mL / g enables a moderate increase in drug blood concentration,
It was confirmed that it was difficult to achieve high absorption.

Comparative Example 2 To 100 mg of MCC (manufactured by Asahi Kasei), 3 mL of a physiological saline solution of carboxyfluorescein was added and stirred, and after 24 hours, the concentration of the supernatant obtained by centrifuging the base was measured. Based on this, the adsorption constant Kp was calculated in physiological saline. Table 3 shows the results.

[0035]

[Table 3]

In Comparative Example 2, a powder composition containing carboxyfluorescein as a main drug model and MCC as a base was prepared. At this time, the base material should be classified into 25-63mm,
The main drug model and the base were mixed in a mortar at a mixing ratio of 1: 100. 15 mg of each of these compositions was administered to the nasal cavity of a white native male rabbit (body weight: 2.5 to 3.0 kg) using a powder administration device (manufactured by Teijin Limited: Publyzer). After a certain period of time, blood was collected from the ear vein, and the blood concentration of the active drug model was measured by a fluorescence detector of HPLC.

Based on the measurement results, the dose of the active drug model was determined.
The result converted to 100 mg is shown in FIG. In Comparative Example 2, the highest blood concentration was shown immediately after administration. From the above results, even when the adsorption constant Kp was within the range of 5-400 mL / g, the drug that did not form a gel showed a moderate drug blood concentration. It was difficult to achieve the rise.

[Brief description of the drawings]

FIG. 1 shows the time course of the drug blood concentration in Examples 1 and 2.

FIG. 2 shows the time course of drug blood concentration in Example 3.

FIG. 3 shows the time course of drug blood concentration in Comparative Example 1.

FIG. 4 is a time-dependent change in drug blood concentration in Comparative Example 2.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Yasuhide Uejima 4-3-2 Asahigaoka, Hino-shi, Tokyo Teijin Limited Tokyo Research Center F-term (reference) 4C076 AA29 BB25 CC01 CC03 CC04 CC05 CC07 CC11 CC13 CC15 CC16 CC21 CC22 CC27 CC29 CC30 EE06 EE09 EE11 EE13 EE16 EE32 EE38 EE48 FF31 FF34 FF68 4C084 AA27 MA05 MA43 MA59 NA10 NA12 ZA011 ZA012 ZA051 ZA052 ZA061 ZA062 ZA081 ZA082 ZA181 ZA182 ZA361 ZA362 ZA401 ZA402 ZA421 ZA422 ZA431 ZA432 ZA541 ZA542 ZA611 ZA612 ZA621 ZA622 ZA711 ZA712 ZB021 ZB022 ZB031 ZB032 ZB111 ZB112 ZB131 ZB132 ZB261 ZB262 ZC031 ZC032 ZC041 ZC042 ZC061 ZC062 ZC081 ZC082 ZC101 ZC102 ZC111 ZC112 ZC131 ZC132 ZC221 ZC222 4C206 AA01 AA02 MA05 MA05 MA05 MA05

Claims (9)

[Claims] 1. A powdery composition for nasal administration comprising a drug and a hydrogel-forming base. 2. The powdery material according to claim 1, wherein the hydrogel-forming base has sufficient strength to maintain its shape as particles even after it has absorbed water and reached equilibrium. A composition for nasal administration. 3. The strength of the hydrogel-forming base, which retains the shape of particles while staying in the nasal cavity in the process of absorbing water after administration to the nasal cavity and forming a gel. The powdery composition for nasal administration according to claim 1 or 2, which is a base having: 4. The hydrogel-forming base physically adsorbs a drug, and has an adsorption constant Kp of 5 to 400 m in physiological saline.
The powdery composition for nasal administration according to any one of claims 1 to 3, which is a base having an L / g. 5. The hydrogel-forming base is selected from the group consisting of lower alkyl ethers of cellulose, starch acrylate, crospovidone, carboxyvinyl polymer, polyvinyl alcohol, aminoalkyl methacrylate copolymer, and methacrylic acid copolymer. The powdery composition for nasal administration according to any one of claims 1 to 4, which is one or more bases. 6. The lower alkyl ether of cellulose is hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium hydroxypropylmethylcellulose, methylcellulose sodium, sodium hydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose calcium, hydroxypropylmethylcellulose calcium, methylcellulose calcium, 1 to 2 selected from the group consisting of ethylcellulose calcium and carboxymethylcellulose calcium
6. The powdery composition for nasal administration according to any one of the above ranges 1 to 5. 7. The powder according to any one of claims 1 to 6, wherein the drug is a drug selected from the group consisting of a non-peptide, a protein drug, and a peptide / protein drug having a molecular weight of 30,000 or less. Nasal composition. 8. The non-peptide / proteinaceous drug may be an anti-inflammatory steroid, an analgesic / anti-inflammatory, an antitussive expectorant, an antihistamine,
Antiallergic drugs, bronchodilators, antiemetics, migraines, sleep inducers, sedatives, vitamins, sex steroid hormones, antitumor drugs, antiarrhythmic / hypertensive drugs, vasopressors, angina drugs, blood vessels The powdery nasal administration according to claim 7, which is at least one selected from the group consisting of a dilator, an antithrombotic, an anxiolytic / psychotropic, an antiepileptic, an antiulcer, an inotropic, and an analgesic. Composition. 9. The peptide / proteinaceous drug may be a luteinizing hormone-releasing hormone, a growth hormone-releasing factor, a somatostatin derivative, a vasopressin, an oxytocin, a hirudin derivative, an enkephalin, an adrenocorticotropic hormone derivative, Bradykinin derivatives, calcitonins, insulins, glucagon derivatives, growth hormones, growth hormone releasing hormones, luteinizing hormones, insulin-like growth factors, calcitonin gene-related peptides, atrial natriuretic peptide derivatives, interferon Erythropoietin, granulocyte colony stimulating factor, macrophage stimulating factor, parathyroid hormones, parathyroid hormone releasing hormone, prolactin, thyroid stimulating hormone releasing hormone,
The powdery nasal administration composition according to claim 7, which is at least one member selected from the group consisting of angiotensins and prostaglandins.