JPH06100436A - Topically remedial pharmaceutical - Google Patents

Abstract

PURPOSE:To provide the subject pharmaceutical improved in the residence of the drug therein at topically applied sites, thus improving bioavailability of the drug. CONSTITUTION:The objective pharmaceutical comprising (A) suspended particles of a water-soluble polymer soluble or gellable in the pH range of secretion from topical sites of the body and (B) a drug applicable onto such topical sites. This pharmaceutical can be produced easily and economically compared with e.g. the preparation of microspheres.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an aqueous local therapy comprising suspended particles of a water-soluble polymer which dissolves or gels in the pH range of a secretory fluid secreted locally in a living body, and a drug which can be applied locally. Regarding the formulation. More specifically, the present invention relates to the pH of the secretory fluid secreted locally in the body for the locally applicable drug.
The coexistence of suspended particles of a water-soluble polymer that dissolves or gels in the region causes the polymer to dissolve or gel depending on the pH of the secretory fluid at the administration site, increasing the viscosity of the drug and The present invention relates to an aqueous topical therapeutic preparation which enhances the retention effect of the drug and enhances the bioavailability of the drug.

[0002]

2. Description of the Related Art An ointment treatment method is used as one of the local therapies. For example, the use in a site covered with mucous membranes such as eyes, ears, or nose is due to the problem of external irritation. Infrequent. Therefore, in these sites, the current practice is to use an aqueous solution or suspension of a drug directly to the treated site to instill, instill or nasally. However, in the case of eye drops, a solution close to half of the drops is spilled from the lower eyelid immediately after instillation, and the rest of the solution also flows into the nasal cavity within a short time. Many of the nasal drops are also removed from the nasal cavity into the pharynx, so that the effective concentration of the drug can remain locally for a relatively short time. For this reason, the bioavailability of the drugs of these therapies is extremely low, and it is necessary to increase the frequency of administration depending on the drugs.

In the field of ophthalmology, when various viscous bases are added to eye drops to increase the kinematic viscosity, the intraocular transfer of the eye drops and the pharmacological effect are increased. Although it is known to be well retained in the eye, these means alone have not yet significantly increased the bioavailability of the drug.

Therefore, in order to enhance the bioavailability of drugs, the development of drug delivery systems for local therapy has been advanced in recent years. Among them, H. W. Hui et al. [International Jo
urinal of Pharmaceuticals, 26
Vol. 203-213 (1985)], describes that cross-linked acrylic acid polymer microspheres containing progesterone improve the migration of progesterone to the anterior aqueous humor. In addition, Minoru Nishimura [Journal of the Japanese Society of Chemotherapy, Vol. 39, p. 728 (1991)] showed that microspheres containing dipekacin could be a new continuous topical therapeutic agent for infections in the ENT region. It suggests.

These microspheres have the advantage that they can be easily instilled, eared or nasalized by the same method as general suspension eye drops, ear drops or nasal drops. However, contrary to the optimum particle size of suspended particles depending on the administration site,
Microspheres having an arbitrary uniform particle size have drawbacks such as that they are not easy to prepare and it is difficult to remove the residual solvent used during preparation. Furthermore, in encapsulating the drug in the microspheres, it is necessary to prepare the microspheres so that the expected drug effect is exhibited without reduction and the effect continues. However, V. Vidmar et al. [Jo
urinal of Microencapsulati
, Vol. 2, pp. 289-292 (1985)], water-soluble drugs and the like rapidly elute from microspheres, and their significance as sustained-release preparations only immediately after preparation of microsphere suspensions. It is the current situation that even if you do not do it.

[0006]

In view of the present situation as described above, the present inventors have sought a local therapeutic preparation which is simpler than the preparation of microspheres and has high bioavailability of a drug locally applied. We have earnestly studied.

As a result, the present inventors have found that the p
When a water-soluble polymer that dissolves or gels in the H region is applied to the local site as an aqueous suspension, the water-soluble polymer is retained as suspended particles at the administration site after administration, and the secretory fluid of the local site is further retained. It was found that the water-soluble polymer dissolves or gels. Furthermore, the present inventors have surprisingly found that the properties of these water-soluble polymers are such that when they are applied in the presence of a drug in a suspension agent of these water-soluble polymers, the retention of the drug at the topical application site is The present invention has been completed by finding that it is possible to provide a new topical therapeutic preparation capable of improving the bioavailability of a drug.

[0008]

That is, the present invention comprises suspended particles of a water-soluble polymer which dissolves or gels in the pH range of a secretory fluid secreted locally in a living body, and a drug which can be applied locally. Is an aqueous topical therapeutic preparation.

The water-soluble polymer used in the present invention is the pH of the secretory fluid secreted locally in the living body of the present invention, such as tears (pH 7.0 to 8.3), nasal discharge (generally pH 5.0 to 5.0).
8.0), otorrhea (generally pH 5.0 to 8.0), or any other substance that dissolves or gels, for example, about pH.
Those that dissolve or gel at 5 to about pH 8 can be advantageously used.

The water-soluble polymer that dissolves in the pH range of the secretory fluid secreted locally in the living body used in the topical therapeutic preparation of the present invention is, for example, a water-soluble polymer that dissolves at about pH 5 or higher, such as hydroxy. Examples thereof include esters of alkyl cellulose and dicarboxylic acid and derivatives thereof, acrylic acid resins and the like. As the ester of hydroxyalkyl cellulose and dicarboxylic acid and its derivative, it is preferable to use hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate and the like. Further, as the acrylic acid-based resin, polymers of methacrylic acid / acrylic acid ester copolymer and polymers of methacrylic acid / methacrylic acid ester copolymer, for example, those commercially available under the trade names of Eudragit L and Eudragit S are conveniently used. Can be used. These water-soluble polymers may be used alone or as a mixture of two or more kinds.

The amount of the water-soluble polymer dissolved in the pH range of the secretory fluid secreted locally in the living body used in the topical therapeutic preparation of the present invention is appropriately determined depending on its type and the type of drug to be blended. Both are usually 0.05 to 30 w /
It is advisable to add about v%, preferably about 0.1 to 10 w / v%.

The average particle size of the fine particles of the water-soluble polymer that is soluble in the pH range of the secretory fluid secreted locally in the body used in the topical therapeutic preparation of the present invention is appropriately determined depending on the administration method and administration site. However, usually 0.1 to 400 μm
Is preferably in the range of 1 to 200 μm.

The method for producing fine particles of a water-soluble polymer that dissolves in the pH range of the secretory liquid secreted locally in the living body used in the topical therapeutic preparation of the present invention is a pulverization method, a spray drying method, an in-liquid drying method, etc. Any of the commonly used methods can be used as appropriate. The fine particles thus obtained can be dispersed in a liquid by a usual method.

In the topical therapeutic preparation of the present invention, the residence time at the application site should be adjusted appropriately depending on the type, concentration and particle size of the water-soluble polymer that dissolves in the pH range of the secretory fluid secreted locally in the living body. You can

The therapeutic drug to be incorporated in the topical therapeutic preparation of the present invention may be a water-soluble drug and / or a poorly soluble drug, and can be advantageously used as long as it is a drug generally used locally. For example, diphenhydramine hydrochloride, chlorpheniramine maleate, glycyrrhizin, sodium cromoglycate, antiallergic agents such as amlexanox, nafazoline nitrate, oxymetazoline hydrochloride, phenylephrine hydrochloride and other vasoconstrictors, fluorometholone, dexamethasone, cortisone, prednisolone and the like. Steroidal anti-inflammatory agents, azulene, indomethacin, nonsteroidal anti-inflammatory agents such as pranoprofen, cephalosporins, erythromycin, cefmenoxime, chloramphenicol, gentamicin, kanamycin and other antibacterial agents,
Local anesthetics such as procaine hydrochloride and lidocaine hydrochloride, β-blockers such as timolol maleate, carteolol hydrochloride and bupranolol hydrochloride, miotic agents such as pilocarpine hydrochloride, distigmine bromide and physostigmine sulfate, atropine sulfate and phenylephrine hydrochloride Ophthalmic agents, and therapeutic agents for cataracts such as pyrenoxine and glutathione.

Of these drugs, the sparingly soluble drug may be solubilized with a solubilizing agent or the like before use, or may be used by suspending it. Examples of the solubilizing agent include surfactants such as polysorbate 80, polyvinylpyrrolidone,
Examples thereof include water-soluble polymers such as polyvinyl alcohol and complex-forming substances such as cyclodextrin.

In these formulations, additives usually used in aqueous liquid preparations such as preservatives (paraoxybenzoic acid esters, benzalkonium chloride, chlorobutanol, etc.), stabilizers (sodium ethylenediaminetetraacetate, sodium citrate, etc.) ), Suspending agents (carboxymethyl cellulose, hydroxypropyl cellulose, etc.), isotonic agents (sodium chloride, sorbitol, glycerin, etc.), surfactants (polysorbate 80, etc.), buffering agents (sodium dihydrogen phosphate, boric acid) , Citric acid, etc.) and a pH adjuster (hydrochloric acid, acetic acid, sodium hydroxide, etc.) may be added as appropriate.

The topical therapeutic preparation of the present invention should be prepared by an ordinary method as an aqueous preparation which is usually used for the treatment of diseases such as ophthalmology and otolaryngology, for example, eye drops, ear drops, nasal drops and the like. You can

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples to clarify the effects of the present invention. However, these are merely examples and the scope of the present invention is limited by these. Not a thing.

[0020]

[Example 1] Eye drops Fluorometholone 0.1 g Hydroxypropyl methylcellulose acetate succinate 1.0 g Sodium dihydrogen phosphate 0.1 g Sodium chloride 0.9 g Polysorbate 80 0.2 g Benzalkonium chloride 0.005 g Distilled water Total 100 ml Distilled water About 80 ml, sodium dihydrogen phosphate (0.1
g), sodium chloride (0.9 g), polysorbate 8
0 (0.2 g) and benzalkonium chloride (0.00
Dissolve 5 g). The obtained liquid was added with 0.1 N hydrochloric acid to p
After adjusting H to about 4.5, fluorometholone (0.1 g)
And hydroxypropylmethylcellulose acetate succinate (1.0 g) having a particle size of about 2 μm,
Add distilled water to make 100 ml and use it as an eye drop.

[Example 2] Eye drops Fluorometholone 0.02 g Hydroxypropyl-γ-cyclodextrin 4.0 g Hydroxypropyl methylcellulose acetate succinate 1.0 g Glycerin 2.6 g Polysorbate 80 0.2 g Sodium dihydrogen phosphate 0. 1 g Benzalkonium chloride 0.005 g Distilled water Total 100 ml Distilled water Approximately 80 ml, fluorometholone (0.02 g)
And hydroxypropyl-γ-cyclodextrin (4.0 g) were dissolved, and sodium dihydrogen phosphate (0.1 g), glycerin (2.6 g), polysorbate 80 (0.2 g) and benzalkonium chloride (0 g) were further dissolved. ．
005 g) is dissolved. After adjusting the pH of the obtained liquid to about 4.5 with 0.1 N hydrochloric acid, hydroxypropylmethylcellulose acetate succinate (1.0 g) having a particle diameter of about 2 μm was dispersed, and distilled water was added to make 100 ml, Use as eye drops.

[Example 3] Ear drops Kanamycin sulfate 2.0 g Hydroxypropylmethyl cellulose phthalate 5.0 g Sodium dihydrogen phosphate 0.1 g Sodium chloride 0.9 g Methyl paraoxybenzoate 0.02 g Propyl paraoxybenzoate 0. 01 g Distilled water Total 100 ml Distilled water About 80 ml is heated and sodium chloride (0.9 ml
g), methyl paraoxybenzoate (0.02 g) and propyl paraoxybenzoate (0.01 g) are dissolved,
After cooling, kanamycin sulfate (2.0 g) and sodium dihydrogen phosphate (0.1 g) are further dissolved. After adjusting the pH of the obtained solution to about 4 with 0.1 N hydrochloric acid, the particle size is adjusted to about 1
Disperse 0 μm hydroxypropylmethylcellulose phthalate (5.0 g), add distilled water to 100 ml, and use this as an ear drop.

[Example 4] Nasal solution Sodium cromoglycate 2.0 g Eudragit L 0.5 g Sodium ethylenediaminetetraacetate 0.01 g Benzalkonium chloride 0.04 g Sodium dihydrogen phosphate 0.1 g Distilled water Total amount 100 ml Distilled water About 80 ml of sodium cromoglycate (2.
0 g), sodium ethylenediaminetetraacetate (0.01
g), benzalkonium chloride (0.04 g) and sodium dihydrogen phosphate (0.1 g) are dissolved. After adjusting the pH of the obtained solution to about 4.5 with 0.1 N hydrochloric acid, Eudragit L (0.5 g) having a particle size of about 1 μm was dispersed,
Add distilled water to make 100 ml and use it as a nasal drop.

[0024]

[Experimental Example] Transferability test of fluorometholone ophthalmic solution to conjunctival tissue (experimental method) The fluorometholone ophthalmic solution prepared in Example 1 was used as a test ophthalmic solution A. 50 μl of the eye drop A was applied to a rabbit, and the concentration of fluorometholone in the conjunctiva was measured with high performance liquid chromatography over time. As a control, Odomer 0.1% ophthalmic solution [registered trademark, manufactured by Senju Pharmaceutical Co., Ltd .; containing fluorometholone (0.1 w / v%)] was used.

(Experimental Results) FIG. 1 shows a time-dependent curve of the concentration of fluorometholone in the conjunctiva. Control and eye drops A
The AUC (area under the concentration-time curve) of each eye drop was calculated from the concentration-time change curve of. In the control, the concentration of fluorometholone in the conjunctiva reached its maximum 2 hours after the instillation, and then disappeared promptly. Compared with the control, the concentration of fluorometholone in the conjunctiva at the time of maximum was lower in the eye drop A than in the control, but the concentration of fluorometholone in the conjunctival tissue (1 mg) remained 0.184 ng until 16 hours after the instillation. Was about 1.7 times that of the control.

From the above, when hydroxypropylmethylcellulose acetate succinate is suspended in eye drops, retention of the drug in the anterior segment of the eye is improved, and
It has been found that the bioavailability of fluorometholone is enhanced.

[0027]

INDUSTRIAL APPLICABILITY The topical therapeutic preparation of the present invention can improve the retention of the drug at the site of local application and enhance the bioavailability of the drug. Further, the topical therapeutic preparation of the present invention can be produced simply and economically as compared with the preparation of microspheres.

[Brief description of drawings]

FIG. 1 is a graph showing a time-dependent curve of fluorometholone concentration in a rabbit conjunctiva after instillation of a test ophthalmic solution A of fluorometholone or a control ophthalmic solution. The horizontal axis represents the time (hour) after instillation, and the vertical axis represents the amount of fluorometholone (mg) per mg of conjunctival tissue. Each value shows an average value (the number of cases is 4).

[Explanation of symbols]

 ○ Control ● Test eye drop A

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 47/32 C 7433-4C 47/38 F 7433-4C E 7433-4C C 7433-4C

Claims (5)

[Claims] 1. An aqueous topical therapeutic preparation comprising suspended particles of a water-soluble polymer that dissolves or gels in the pH range of a secretory fluid secreted locally in a living body, and a drug that can be applied locally. . 2. The preparation according to claim 1, wherein the water-soluble polymer is at least one substance selected from an ester of hydroxyalkyl cellulose and dicarboxylic acid and its derivative, and an acrylic acid resin. 3. The preparation according to claim 2, wherein the ester of hydroxyalkyl cellulose and dicarboxylic acid and its derivative are at least one compound selected from hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate. 4. The preparation according to claim 2, wherein the acrylic acid resin is at least one compound selected from methacrylic acid / acrylic acid ester copolymer and methacrylic acid / methacrylic acid ester copolymer. 5. The preparation according to claim 1, 2, 3 or 4, wherein the local therapeutic preparation is an eye drop, an ear drop and a nasal drop.