JPH08151332A - Aqueous suspension for nasal drop - Google Patents

Abstract

PURPOSE: To provide an aqueous suspension for nasal drop which contains cyclodextrin and a water-slightly soluble medicine having low stability to cyclodextrin, thus having improved retention on the nasal membrane of the medicine with effect duration prolonged. CONSTITUTION: A slightly soluble medicine for local treatment having 1,000 or lower, preferably 300 or lower stability constant to cyclodextrin is suspended in an aqueous solution of 0.1-10wt.% cyclodextrin. The slightly soluble medicine is, for example, steroidal anti-inflammatory non-steroidal inflammatory antihistaminic agent, antiallergic agent, or antimicrobial agent. Cyclodextrin is used in an amount of 1-10 moles per mole of the medicine and other known nasal additives are added and the pH of the suspension is adjusted to 5-7. The suspension is dripped or sprayed.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aqueous nasal suspension of a drug which is poorly soluble in water. More specifically, it relates to an aqueous nasal suspension containing cyclodextrin and a poorly water-soluble drug having a stability constant for cyclodextrin of 1000 or less.

[0002]

2. Description of the Related Art Nasal drops are generally administered in the form of solutions or powders. However, the drug administered as a liquid drug is flowed down to the pharynx in a relatively short time after administration, or is mixed with nasal discharge and is naturally excreted from the nostril. When administered in the form of powder, the particle size of the powder is 10
When the particle diameter is 500 μm or less, the particles migrate to the bronchial part, and when the particle diameter is 500 μm or more, the particles are deposited in the villus-free part of the anterior part of the nose and are not stored in the mucous membrane with villi, and thus have a medicinal effect. There was a problem that was not played. Therefore, in order to exert the medicinal effect of nasal drops, frequent administration was necessary. However, frequent administration of nasal drops results in a chronic edematous lesion of the nasal mucosa often referred to as drug-induced rhinitis. Therefore, there has been a long-awaited need for the development of a nasal drop that maintains the retention of the drug in the nasal mucosa and prolongs the action time of the drug.

Cyclodextrins are cyclic oligosaccharides, which have the property of incorporating various compounds into a hydrophobic cavity to form a water-soluble complex as an inclusion compound, improving the solubility and stabilizing of drugs. Since it is a compound utilized for the above purpose, it is used for preparing a poorly water-soluble drug into a liquid preparation such as an injection solution or an eye drop solution. Further, it is said that the compound having cyclodextrin clathrated is gradually released from the clathration site, so that the duration of action of the drug is prolonged. Such cyclodextrins are α-, β-
There are two types, γ-type and γ-type, each having different properties, but the main research is to use β- or γ-cyclodextrin and its derivatives to solubilize and stabilize poorly water-soluble drugs. There are many reports (for example, Japanese Patent Publication No. 6-43314, Japanese Patent Publication No. 5-70612,
JP-A-3-11018, JP-A-5-178765, JP-A-4-134093, JP-A-2-167228).

Also for nasal drops using cyclodextrins, for example, a pharmaceutical composition of a poorly water-soluble antiviral agent adapted to the cavity of cyclodextrin by utilizing the above-mentioned properties of cyclodextrin (Japanese Patent Laid-Open No. 64-64- 4531
9) and a nasally-administered preparation of a polypeptide having poor gastrointestinal absorbability and cyclodextrin (Japanese Patent Publication No. 2-19092). However, a drug having a stability constant with respect to cyclodextrin of 1000 or less and poorly soluble in water is not included in cyclodextrin or very difficult to be included in cyclodextrin, and is difficult to be dissolved in water. It is not suitable for solubilization and stabilization and therefore its utility as a pharmaceutical preparation with cyclodextrin, especially as a nasal drop, has not yet been investigated.

[0005]

In view of the current situation,
The present inventors have conducted intensive studies on an aqueous nasal suspension of a poorly water-soluble drug, which improves the nasal mucosal retention of the drug and prolongs the action time of the drug locally.

[0006]

As a result, when a sparingly water-soluble drug having a low stability constant for cyclodextrin is suspended in an aqueous solution of cyclodextrin and nasally applied, a pharmacological effect of the sparingly water-soluble drug is unexpectedly exerted locally. Was markedly increased and the pharmacological effect was sustained. The present invention has been completed based on this new finding.
That is, the present invention relates to an aqueous nasal suspension containing cyclodextrin and a poorly water-soluble drug having a stability constant for cyclodextrin of 1000 or less.
Here, the stability constant is an index indicating the stability of the complex of cyclodextrin and the drug, and also indicates the extent to which the complex is formed from the cyclodextrin and the drug. The stability constant between the drug and cyclodextrin in the present invention is such that the drug concentration is kept constant and 200 times / min at 25 ° C. with various concentrations of cyclodextrin solutions.
Shake for 24 hours on a shaker to prepare a solubility phase diagram of saturated drug in cyclodextrin solution and analyze the solubility method of Higuchi et al. (Advances in Analytical Chemistry and Instrument
entation, Volume 4, pages 144-148, 1965).

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The cyclodextrin used in the present invention includes α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and dimethyl-β-cyclodextrin and hydroxypropyl-γ which are derivatives of these cyclodextrins. -Any one such as cyclodextrin can be used. Among these cyclodextrins, α-cyclodextrin having a low stability constant with various drugs and an extremely low ratio of forming an inclusion compound is particularly preferable. These cyclodextrins are usually dissolved in water at 1.0 to 10.0 w / v%, preferably 2.5 to 7.5 w / v%, and may be used alone or in admixture of two or more depending on the purpose. Can be used. The poorly water-soluble drug used in the present invention is 25
Purified water required to dissolve 1 g of a drug at 1 ° C and 1 atm is usually 1000 ml or more, preferably 10000 ml or more, more preferably 100000 ml or more. It is a term showing solubility in the Japanese Pharmacopoeia. There are certain "extremely insoluble" and "almost insoluble" (12th Revised Japanese Pharmacopoeia Manual, General Rules A-45, Hirokawa Shoten,
1991).

The poorly water-soluble drug used in the present invention is preferably a poorly water-soluble drug having a stability constant with respect to cyclodextrin of usually 1,000 or less, preferably 500 or less, more preferably 300 or less. Use of nasal drops Depending on the purpose, it is appropriately selected from steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antihistamines, antiallergic agents, antibacterial agents and the like. Among such poorly water-soluble drugs, examples of steroidal anti-inflammatory agents include loteprednol etabonate, fluorometholone, hydrocortisone, betamethasone, beclomethasone propionate, and fluticasone propionate. Examples of the nonsteroidal anti-inflammatory agent include mefenamic acid and the like. Examples of the antihistamine include clemastine fumarate and terfenadine. Examples of the antiallergic agent include tranilast. Examples of the antibacterial agent include antibiotics such as erythromycin and tetracycline, and chemotherapeutic agents such as sulfamethizole, sulfamethoxazole and sulfisoxazole.

These poorly water-soluble drugs are usually contained in 0.01-1.
0.0 w / v%, preferably 0.05-5.0 w / v
%, More preferably 0.1 to 1.0 w / v%, suspended in water and used alone or in combination of two or more depending on the purpose of the nasal drop. The aqueous nasal suspension of the present invention is advantageous in that these poorly water-soluble drugs are used after being adjusted within the range of the particle size normally used for nasal drops,
The particle size is usually 1.0 to 100 μm, preferably 5.
It is 0 to 50 μm. The mixing ratio of the cyclodextrin and the poorly water-soluble drug is appropriately determined according to the stability constant of the cyclodextrin and the drug, etc. Usually, the cyclodextrin is usually added to 1 mol of the poorly water-soluble drug. It is preferably used in a proportion of 0.0 to 10.0 mol, preferably 2.5 to 7.5 mol. Specifically, for example, α
In the case of cyclodextrin, the stability constant for α-cyclodextrin is 1 mol of a drug having a stability constant of 200 or less,
α-cyclodextrin is usually 1.0 to 10.0 mol,
It is preferable to add 2.5 to 7.5 mol.

The aqueous nasal suspension of the present invention may contain additives generally used for known nasal drops. As such additives, for example, preservatives, isotonic agents, buffers, stabilizers, pH adjusters, thickeners and suspending agents are used. Preservatives include parabens (methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), reverse soaps (benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, etc.), alcohol derivatives (phenethyl alcohol, etc.) ), Organic acids and salts thereof (sodium dehydroacetate, sorbic acid and salts thereof, etc.), phenols (parachloromethoxyphenol, parachlorometacresol, etc.) and organic mercurial agents (thimerosal, phenylmercuric nitrate, nitromesol, etc.) Can be mentioned. Examples of the tonicity agent include sodium chloride, sorbitol, mannitol and the like. Examples of the buffer include boric acid and its salts, phosphates, acetates and amino acid salts. Examples of the stabilizer include antioxidants (sodium sulfite, sodium bisulfite, sodium metabisulfite, etc.) and chelating agents (sodium edetate, citric acid and salts thereof, etc.) and the like. Examples of pH adjusters include hydrochloric acid, acetic acid, sodium hydroxide, phosphoric acid and the like. Examples of the thickener include sugars (sorbitol, mannitol, sucrose, etc.), celluloses (methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, etc.) and synthetic polymer compounds (polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, etc.) Etc. As the suspending agent, the above celluloses, synthetic polymer compounds and surfactants (4th
And cationic surfactants such as primary ammonium salts, anionic surfactants such as alkylsulfates, and amphoteric surfactants such as lecithin).

The amount of these additives used varies depending on the active ingredient and the amount used, but it is usually desirable to approximate the physiological condition of the nose (isotonic with nasal discharge). For example, the osmotic pressure is 0.2-4. 0.0 w / v% saline solution, preferably 0.5 to 2.0 w / v% saline solution, more preferably 0.9 to 1.5 w / v% saline solution. It is the corresponding range. The poorly water-soluble drug used in the present invention is required to be poorly water-soluble in the present nasal drop suspension, and therefore, the solubility of the poorly water-soluble drug in the suspension should be controlled. The use of additives in amounts which exert their effect outside the definition of the specification should be avoided.

The aqueous nasal suspension of the present invention is advantageously adjusted and used within the pH range normally used for nasal administration, and it is usually preferred to adjust the pH to 5 to 7 before use. The aqueous nasal suspension of the present invention is advantageously adjusted to an osmotic pressure range usually used for nasal drops, and is usually 14
It is used after adjusting to 0 to 1140 mOsm, preferably 200 to 870 mOsm, and more preferably 280 to 310 mOsm. The aqueous nasal suspension of the present invention is advantageously used by adjusting the viscosity within the range usually used for nasal drops, and is usually adjusted to 800 cSt or less, preferably 600 cSt or less. In addition, the aqueous suspension for nasal drop of the present invention may be added with appropriate amounts of other pharmaceutical ingredients such as vasoconstrictor and surface anesthetic. Examples of the vasoconstrictor include naphazoline nitrate, phenylephrine hydrochloride and the like. Examples of the surface anesthetic include lidocaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride and the like.

The aqueous nasal suspension of the present invention can be produced by a method known per se. For example, the 9th Revised Dispensing Guidelines (edited by the Japanese Association of Pharmacists, pages 128-129, published by Yakuji Nippo)
And the like. The thus-obtained aqueous nasal suspension of the present invention is capable of increasing the local pharmacological effect by improving the nasal mucosal retention of a poorly water-soluble drug, and sustaining the pharmacological effect. The frequency can be reduced and patient compliance can be improved. The aqueous nasal suspension of the present invention can be used according to a method generally used for known nasal drops, for example, a spraying method and a dropping method. When the spray method is used, the nasal suspension of the present invention may be used for the treatment of adult allergic rhinitis and vasomotor rhinitis, although it depends on, for example, age, weight, and symptoms, and beclomethasone propionate may be used. Of 0.05 to 0.5 w / v%, preferably 0.1 to 0.2
It is advisable to adjust the dose to 5 w / v%, and spray it by inhalation into the nasal cavity once or twice a day once or twice with a nebulizer. In the case of the dropping method, for example, depending on the age, weight, symptoms, etc., to use the aqueous nasal suspension of the present invention for the treatment of adult allergic rhinitis, the concentration of loteprednol etabonate is 0.1 to 1.0 w / v%, preferably 0.25 to 0.5 w / v%, which is applied once or twice a day once or twice in a standing or sitting position. Bend over the neck and drip through the nostril.

[0014]

EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples below to clarify the effects of the present invention.
These are merely examples, and these do not limit the scope of the present invention.

[Example 1] Suspended nasal solution containing loteprednol etabonate Roteprednol etabonate 0.5 g α-cyclodextrin 5.0 g Sodium chloride 0.9 g Sodium acetate 0.1 g Sodium edetate 0.02 g Chloride Benzalkonium 0.005 g Sterile purified water 100.0 ml After stirring the above formulation overnight, the pH was adjusted to 5.0 with hydrochloric acid.

Example 2 Suspended Nasal Solution Containing Roteprednol Ethabonate Loteprednol Ethabonate 0.5 g β-Cyclodextrin 1.8 g Sodium Chloride 0.9 g Sodium Acetate 0.1 g Sodium Edetate 0.02 g Chloride Benzalkonium 0.005 g Sterile purified water 100.0 ml After stirring the above formulation overnight, the pH was adjusted to 5.0 with hydrochloric acid.

Example 3 Suspended Nasal Solution Containing Fluorometholone Fluorometholone 0.1 g γ-Cyclodextrin 4.0 g Sodium Chloride 0.8 g Sodium Dihydrogen Phosphate 0.1 g Benzalkonium Chloride 0.01 g Sterile Purified Water 100.0 ml After stirring the above formulation overnight, the pH was adjusted to 7.
Adjusted to 0.

Example 4 Tranilast-containing Suspended Nasal Solution Tranilast 0.1 g α-Cyclodextrin 4.0 g Sodium Chloride 0.8 g Sodium Dihydrogen Phosphate 0.1 g Benzalkonium Chloride 0.01 g Sterile Purified Water 100. 0 ml After stirring the above formulation overnight, pH 7 with sodium hydroxide.
Adjusted to 0.

Example 5 Suspended Nasal Solution Containing Beclomethasone Propionate Beclomethasone Propionate 0.5 g α-Cyclodextrin 5.0 g Sodium Chloride 0.8 g Sodium Dihydrogen Phosphate 0.1 g Benzalkonium Chloride 0.01 g Sterilized Purified water 100.0 ml After stirring the above formulation overnight, the pH was adjusted to 6.3 with hydrochloric acid.

Example 6 Suspended Nasal Solution Containing Mefenamic Acid Mefenamic Acid 0.5 g α-Cyclodextrin 5.0 g Sodium Chloride 0.8 g Sodium Acetate 0.1 g Benzalkonium Chloride 0.005 g Sterile Purified Water 100.0 ml After stirring the above formulation overnight, the pH was adjusted to 5.8 with hydrochloric acid.

[0021]

[Test example]

[Test Example 1] Stability constant of each drug The concentration of each drug was kept constant, and various concentrations of α-dextrin solutions were used, together with a shaking machine (TAT) at 25 ° C for 200 times / min for 24 hours.
EC BIO-SHAKER BR-40L) was shaken and the solubility phase diagram of the saturated drug in α-cyclodextrin solution was prepared.
And other solubility methods (Advances in Analytical Chemistry and
Instrumentation, vol. 4, pp. 144-148, 1965) 14 of
The stability constants of the drug calculated based on the equation (8) on page 6 are shown in [Table 1].

[0022]

[Table 1]

[Test Example 2] Effect on rat rhinitis model (Test method) Male Wistar rats (body weight 170 g,
20 μl of 0.5 v / v% acetic acid was nasally administered to both nasal cavities of one group (7 to 10 animals) under anesthesia with pentobarbital.
After 10 minutes, 3 μl of 10 w / v% arachidonic acid was intranasally administered,
Inflammation of the nasal mucosa was induced. Four hours after the induction of inflammation, the trachea was incised, a cannula was inserted to secure the airway, and then the esophagus was incised and an elastor tube was inserted from the neck to just before the nasal cavity. Immediately 1 w / v% Evans Blue 1
ml was injected intravenously, and a physiological saline solution containing 5 v / v% formamide was perfused in the nasal cavity for 6 minutes at a flow rate of 10 ml / hr from an elastor tube to collect the leakage fluid from the right and left nasal cavities. The absorbance of the collected liquid was measured at 625 nm. The test solutions were the nasal drops of Example 1 (LTP / α-CyD nasal drops) and the nasal drops obtained by removing α-cyclodextrin from Example 1 (LT
P nasal drops) and 0.5 v / v% acetic acid nasal drops 1 or 15 hours prior to anesthesia for both nasal cavities under pentobarbital anesthesia 10
μl nasal administration was performed. In the control group, a physiological saline solution was nasally applied instead of the test solution.

[0024]

[Table 2]

(Test Results) The results are shown in [Table 2]. When LTP / α-CyD nasal drops were treated 1 hour before the induction of inflammation, the LTP / α-CyD nasal drops administration group significantly suppressed the leakage of pigment from the nasal mucosa. The inhibitory effect was also observed when the nose was applied 15 hours before the induction of inflammation. On the other hand, in the LTP nasal drop administration group, suppression was observed when nasal application was performed 1 hour before inflammation induction, but the effect was not significant, and when nasal application was performed 15 hours before inflammation induction. , Its effect was not recognized. From the above, it has been clarified that the anti-inflammatory effect is enhanced and the effect lasts by adding α-cyclodextrin to loteprednol etabonate.

Test Example 3 Retention Test on Rat Nasal Mucosa (Test Method) Male Wistar rats (body weight 170 g,
10 μl of the test solution was intranasally administered to both nasal cavities of 5 animals per group under anesthesia with pentobarbital. 0.5, 1, 2, after administration
After 4, 6, 8, 12 and 24 hours, whole blood was collected from the abdominal vena cava under pentobarbital anesthesia and nasal mucosa was collected. After the wet weight of the nasal mucosa was measured, loteprednol etabonate was extracted with ethyl acetate, and the loteprednol etabonate in the nasal mucosa was measured by liquid high performance chromatography. As the test liquid, the nasal drops of Example 1 (LTP / α-CyD nasal drops) and the nasal drops obtained by removing α-cyclodextrin from Example 1 (LTP nasal drops) were used.

(Test Results) The results are shown in FIG. The disappearance rate of loteprednol etabonate from the nasal mucosa and the area under the drug concentration (AUC) in the nasal mucosa determined from the results shown in FIG. 1 are shown in Table 3. LT
The disappearance rate of loteprednol etabonate in the P / α-CyD nasal drop administration group was 1/20 as slow as that in the LTP nasal drop administration group,
In addition, the AUC of the LTP / α-CyD nasal drop administration group was about 10 times larger than that of the LTP nasal drop administration group, and the nasal drop containing α-cyclodextrin in loteprednol etabonate suspension was applied to the nasal mucosa. It was clarified that the retention property of was improved.
The disappearance rate is calculated by the following formula. Disappearance rate (hr ⁻¹ ) = ln C ₁ −ln C ₂ / t ₁ −t ₂ t ₁ , t ₂ = time after LTP administration (hr) C ₁ = LTP concentration in nasal mucosa at time t ₁ C ₂ = LTP concentration in nasal mucosa at t ₂

[0028]

[Table 3] In the table, Cmax indicates the highest concentration value among the actually measured values of loteprednol etabonate in 1 mg of nasal mucosal tissue.

[0029]

INDUSTRIAL APPLICABILITY The aqueous nasal suspension of the present invention increases the efficacy of a poorly water-soluble drug, improves nasal mucosal retention, and prolongs the duration of efficacy, thus reducing the number of nasal drops. And can be used as an excellent topical nasal drop to improve patient compliance.

[Brief description of drawings]

FIG. 1 shows the amount of loteprednol etabonate in rat nasal mucosa after nasal instillation.

[Explanation of symbols]

○ indicates LTP / α-CyD nasal drops nasal group and ● indicates LTP nasal drops nasal group.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/40 AEM 31/445 31/57 ABE 31/635 31/65 31/71 ADZ 47/40 N Z

Claims (6)

[Claims] 1. An nasal aqueous suspension comprising cyclodextrin and a poorly water-soluble drug having a stability constant for cyclodextrin of 1000 or less. 2. The poorly water-soluble drug is a local therapeutic drug.
Aqueous nasal suspension as described. 3. The point according to claim 1 or 2, wherein the poorly water-soluble drug is one or more drugs selected from steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antihistamine agents, antiallergic agents and antibacterial agents. Aqueous nasal suspension. 4. A steroidal anti-inflammatory drug is loteprednol etabonate, fluorometholone, beclomethasone propionate and fluticasone propionate; a nonsteroidal anti-inflammatory drug is mefenamic acid; an antihistamine is clemastine and terfenadine fumarate; and an antiallergic drug is Tranilast; The aqueous nasal suspension according to claim 3, wherein the antibacterial agent is one or more drugs selected from erythromycin, tetracycline, sulfamethizole, sulfamethoxazole and sulfisoxazole. 5. A cyclodextrin concentration of 0.1 to 1
It is 0.0 w / v%, The aqueous suspension for nasal drops of any one of Claims 1-4. 6. The nasal drop aqueous suspension according to claim 1, wherein the cyclodextrin is α-cyclodextrin.