JP6050031B2 - Film formulation - Google Patents

Description

  TECHNICAL FIELD The present invention relates to a film preparation, and more particularly to a film preparation containing a drug that exhibits increased solubility in the prior art.

  It is said that a hardly soluble component often has a rate of dissolution that is a rate-limiting factor for absorption in the body, and the difference in solubility significantly affects the bioavailability of a drug. In order to solve such a problem, a sustained-release preparation in which the solubility of the hardly soluble component is improved by blending the hardly soluble component together with the water-soluble polymer and the biodegradable polymer compound is known. (Patent Document 1).

  On the other hand, for example, xerostomia (DM) associated with a decrease in salivary secretion has increased as a side effect of aging and drug treatment, and eating and swallowing disorders and oral infections during DM are problematic. Antifungal drugs such as miconazole are effective for the treatment of such diseases. However, miconazole is a typical poorly soluble component in water. Therefore, conventionally, miconazole has been prescribed as an ointment and often applied directly to the oral cavity of a patient by the hands of a third party such as a nurse or a caregiver. There are concerns about hygiene and other infectious diseases arising from this application.

  One approach from the formulation aspect to solve such problems is film formulation. With this film preparation, a method of applying a target drug to the oral cavity without using a third party is considered.

  Conventionally, as a film preparation containing a hardly soluble component, it is obtained by distilling off a solvent from a mixture of hydroxypropylcellulose, polyvinylpyrrolidone and methylcellulose and water or hydrous ethanol as described in Patent Document 2, and hardly soluble. There are oral patches containing sex drugs. However, even a patch such as that described in Patent Document 2 does not always fully achieve the formulation of a wide range of poorly soluble components, particularly the poorly soluble components such as miconazole.

Japanese Patent Laid-Open No. 5-4924 JP 2006-316209 A

  An object of the present invention is to solve the above-mentioned problems. The object of the present invention is to improve the solubility of a hardly soluble component and to prevent eating and swallowing disorders such as patients with xerostomia. An object of the present invention is to provide a film preparation that can be easily taken even by annoying person.

The present invention is a film preparation containing a hardly soluble component, a surfactant and a film forming material,
The surfactant is at least one compound selected from the group consisting of polyoxyalkylene sugar fatty acid esters, polyoxyalkylene alkyl ethers and polyoxyalkylene ethers, and the film-forming material is alginic acid and its pharmaceuticals And at least one natural selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof, pullulan, pectin, dextran, gelatin, and chondroitin sulfate and pharmaceutically acceptable salts thereof It is a film formulation which is a polysaccharide.

  In one embodiment, the said film forming material is contained in the ratio of 70 mass% to 95 mass% with respect to a film formulation.

  In one embodiment, the poorly soluble component is at least one pharmaceutical component selected from the group consisting of antifungal agents, plant extracts, coenzyme Q10, phytosterols, lipoic acid, terpenes, flavonoids, and phenols. is there.

  In a further embodiment, the surfactant is a polyoxyalkylene sugar fatty acid ester.

  In yet another embodiment, the polyoxyalkylene sugar fatty acid ester is a polyoxyethylene sorbitan fatty acid ester.

  In one embodiment, the film formulation of the present invention is used for buccal application.

  In one embodiment, the film formulation of the present invention is used for external use on the skin.

  According to the present invention, even a poorly soluble component such as the antifungal drug miconazole can provide a film preparation with improved solubility. For example, when this preparation is used as an oral film preparation, it can be easily taken even by a person who suffers from eating / deglutition disorders. As a result, the burden on third parties such as nurses and caregivers can be reduced, and the problems of hygiene and other infectious diseases that have arisen from drug application by the hands of conventional third parties can also be avoided. Furthermore, the film preparation of the present invention is not limited to such an oral use, but is used for transdermal uses such as patches (for example, wound dressings) and cosmetic sheets (for example, lotion pack sheets) (ie, for external use on the skin). It can also be used as a transdermal film formulation for use.

It is a graph which shows the time-dependent change of the quantity of the miconazole eluted from each film when the film produced in Example 1 and the film produced in Comparative Example 1 and 2 were each used for the elution test. It is a graph which shows the time-dependent change of the quantity of the miconazole eluted from each film when the film produced in Example 2 and 3 and the film produced in the comparative example 1 were each used for the elution test.

  The film preparation of the present invention contains a hardly soluble component, a surfactant and a film forming material.

  Slightly soluble components include water or aqueous solutions, or drugs with poor solubility in the body. For example, in the Japanese Bureau of Law or the Japanese Bureau of Pharmaceutical Standards, “Slightly insoluble”, “Insoluble”, “Very soluble” Is difficult ”or“ almost insoluble ”, in other words, the amount of solvent (for example, water) required to dissolve 1 g or 1 mL of this poorly soluble component is, for example, 30 mL or more and less than 100 mL, It is a drug corresponding to any of 100 mL or more and less than 1000 mL or 1000 mL or more. Examples of such poorly soluble components include antifungal agents, plant extracts, coenzyme Q10, phytosterols, lipoic acid, terpenes, flavonoids, and phenols.

  Examples of antifungal agents include azole antifungal agents, and more specific examples include miconazole (MCZ), ketoconazole (KCZ), clotrimazole, econazole, isoconazole, sulconazole, oxyconazole, Croconazole, bifonazole, neticonazole, lanconazole, fluconazole (FLCZ), itraconazole (ITCZ), and voriconazole. These antifungal agents can be in the form of a suitable pharmaceutically acceptable salt (eg, nitrate). Specific examples of plant extracts include organic solvent extracts or supercritical extracts of various plants. Terpenes encompass both terpenes and terpenoids, specific examples include geraniol, nerol, linalool, citral, citronellol, menthol, mint, myrcene, pinene, limonene, terpineol, carvone, yonon, camphor (camphor) , Borneol, Elemen, Casinol, Casinene, Farnesol, Nerolidol, Humurene, Santonin, Phytol, Abietic acid, Geranyl farnesol, Rosmanol, Carnosic acid, Caffeol, Caffe stall, Squalene, Limonin, Camelliagenin, Lanosterol, Oleanolic acid, Ursol Examples include acids, squalene, hopane, betulinic acid, carotenoids, and lycopene. Specific examples of phytosterols include cyclic alcohols such as β-sitosterol, stigmasterol, brassicasterol and campesterol. Specific examples of flavonoids include tiliroside, quercetin, kaempferol, rutin, luteolin and isoflavones. Specific examples of phenols include caffeic acid, chlorogenic acid, ferulic acid, coumaric acid, rosmarinic acid, sesamin, sesaminol, sesamol, curcumin, ellagic acid, coumarin and the like.

  In the present invention, the hardly soluble component may be a combination of one or more. When multiple types of poorly soluble components are combined, the component ratio is not particularly limited, and can be appropriately selected by those skilled in the art.

  Although content of the said hardly soluble component in the film formulation of this invention is not specifically limited, For example, it is 0.05 mass%-20 mass% with respect to a film formulation, Preferably it is 0.1 mass%-10 mass%. . When content of a hardly soluble component is less than 0.05 mass%, there exists a possibility that the medicinal effect of the said hardly soluble component may not fully be exhibited as a film formulation. In addition, if the content of the hardly soluble component exceeds 20% by mass, the hardly soluble component is not uniformly dispersed in the film preparation (for example, partially agglomerated), which affects the quality stability of the product. There is a risk of giving.

  In the film preparation of the present invention, the surfactant is nonionic, and examples thereof include polyoxyalkylene sugar fatty acid esters, polyoxyalkylene alkyl ethers and polyoxyalkylene ethers, and combinations thereof. Specific examples of such surfactants include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan Monooleate, polyoxyethylene sorbitan triisostearate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, poly Oxyethylene stearyl ether, oxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene mysterite Le, suitable HLB (Hydrophilic-hydrophobic balance; Hydrophilic-Lipophilic balance) such as polyoxyethylene octyl dodecyl ether compounds exhibiting the like. In the present invention, the surfactant is preferably a polyoxyalkylene sugar fatty acid ester, and particularly preferably polyoxyethylene sorbitan monooleate.

  Although content of the said surfactant in the film formulation of this invention is not specifically limited, For example, 0.05 mass%-0.5 mass% with respect to a film formulation, Preferably 0.1 mass%-0.5 % By mass. When the content of the surfactant is less than 0.05% by mass, the above-mentioned hardly soluble component is not sufficiently dissolved in the film preparation, and the hardly soluble component is partially aggregated in the film. This may affect the quality stability. On the other hand, if the content of the surfactant exceeds 0.5% by mass, foaming tends to occur during film production, and the appearance and quality stability of the film are impaired, while the solubility of the hardly soluble component itself is further increased. May not improve.

  In the film preparation of the present invention, the film forming material is a natural polysaccharide. Examples of natural polysaccharides include alginic acid and pharmaceutically acceptable salts thereof, hyaluronic acid and pharmaceutically acceptable salts thereof, pullulan, pectin, dextran, gelatin, and chondroitin sulfate and pharmaceutically acceptable salts thereof. Salts, as well as combinations thereof. Alginic acid and pharmaceutically acceptable salts thereof are preferred, and sodium alginate is particularly preferred.

  Although content of the said film formation material in the film formulation of this invention is not specifically limited, For example, they are 70 mass%-95 mass% with respect to a film formulation. When the content of the film-forming material is less than 70% by mass, not only the appearance as a film preparation may not be maintained, but also the above hardly soluble component is not sufficiently dissolved, and the hardly soluble component is partially contained in the film. There is a risk that the quality stability of the product will be affected. Moreover, when content of a film formation material exceeds 95 mass%, there exists a possibility of affecting the quality quality stability as a product.

  The film preparation of the present invention may contain other components in addition to the hardly soluble component, the surfactant and the film-forming material as long as the effects of the present invention are not impaired. Examples of such other components include water-soluble polymer compounds, plasticizers, fragrances, sweeteners and the like.

  Examples of water-soluble polymers include, but are not limited to, gum arabic, sodium alginate, karaya gum, xanthan gum, gellan gum, soy polysaccharide, tragacanth gum, pectin, sodium carboxymethylcellulose (CMC-Na), carboxyvinyl polymer, polyacrylic acid , Polyacrylate (monovalent salts such as Na and K), curdlan, agar, guar gum, glucomannan, tamarind seed gum, tara gum, starch, locust bean gum, hydroxypropyl methylcellulose (HPMC), water-soluble hydroxyethylcellulose ( HEC), polyvinyl alcohol, and dextrin, and combinations thereof

  Examples of plasticizers include, but are not limited to, glycerin, diglycerin, triglycerin, polyglycerin, sorbitol, maltitol, xylitol, polyethylene glycol, propylene glycol, butylene glycol, hexylene glycol, pentylene glycol, polyoxyethylene Polyoxypropylene glycol, and acetylethanolamine, and combinations thereof.

  Examples of flavors include, but are not limited to, mastic oil, parsley oil, peppermint oil, spearmint oil, anise oil, eucalyptus oil, wintergreen oil, cassia oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander Oil, mandarin oil, lime oil, lavender oil, laurel oil, camomile oil, caraway oil, bay oil, lemongrass oil, pine needle oil, neroli oil, rose oil, jasmine oil, iris concrete, absolute peppermint, absolute rose, Natural flavors such as orange flour, as well as l-menthol, dl-menthol, menthol derivatives, dl-camphor, carvone, anethole, methyl salicylate, cinnamic aldehyde, linalool, linalyl acetate, limonene, menthone Ruacetate, pinene, octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allylcyclohexane propionate, methyl anthranilate, ethyl methyl anthranilate, vanillin, undecalactone, hexanal And single-flavoring agents such as ethinone alcohol, propyl alcohol, butanol, isoamyl alcohol, hexenol, dimethyl sulfide, cycloten, furfural trimethylpyrazine, ethyl lactate, and ethylthioacetate.

  Examples of sweeteners include, but are not limited to, sucrose, fructose, glucose, lactose, reduced maltose water candy, powdered reduced maltose water candy, glucose fructose liquid sugar, fructose glucose liquid sugar, honey, sorbitol, maltitol, mannitol , Xylitol, erythritol, aspartame, acesulfame potassium, sucralose, saccharin, and sodium saccharin, and combinations thereof.

  In the film preparation of the present invention, the content of the other components can be appropriately selected by those skilled in the art.

  The film preparation of the present invention has a thickness of, for example, 20 μm to 500 μm, preferably 50 μm to 300 μm. By having such a thickness, for example, even when used as a film preparation for intraoral application, it is possible to avoid the occurrence of an uncomfortable feeling in the oral cavity while maintaining its flexibility. The film preparation of the present invention has, for example, a rectangle of 0.5 cm × 0.5 cm to 10 cm × 10 cm or a circle of 1 cm to 10 cm in diameter.

  The film preparation of the present invention can be produced, for example, as follows.

  First, a predetermined amount of the film-forming material and the other components are mixed with water or an ethanol aqueous solution as a solvent, and a surfactant is charged therein to prepare a base aqueous solution. Next, a predetermined amount of a poorly soluble component is added to this base aqueous solution and stirred sufficiently to obtain a casting solution in which the hardly soluble component is uniformly dispersed.

  The casting solution is cast in a predetermined amount on a release film made of polyethylene terephthalate or polypropylene, and dried to remove the solvent.

  After drying, the film preparation of the present invention can be obtained by cutting into a predetermined size together with the release film.

  In this way, the film preparation of the present invention can be produced.

  The film preparation of the present invention is, for example, a film preparation for oral application (oral film preparation), and a transdermal application such as a patch (for example, a wound dressing), a cosmetic sheet (for example, a lotion pack sheet), etc. It can also be used as a transdermal film formulation for (ie, external use for skin). For this reason, the film preparation of the present invention can be applied to the body surface such as the face, feet, arms, abdomen, and chest as well as in the oral cavity.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

Example 1
A sodium alginate powder (manufactured by Nacalai Tesque Co., Ltd.) having a viscosity of 300 cps (1% aqueous solution) was dissolved in ion-exchanged water to prepare a concentration of 1.5%. To this aqueous solution, as a surfactant, polyoxyethylene sorbitan monooleate (TO-10MV manufactured by Nikko Chemicals Co., Ltd.) was added so that its concentration was 0.5%, and the base was obtained by stirring uniformly. An aqueous solution was obtained.

  10 mg of miconazole nitrate (biochemical reagent grade, manufactured by Wako Pure Chemical Industries, Ltd.) is added to 10 g of this base aqueous solution, and the mixture is stirred and dispersed uniformly for about 10 minutes, followed by ultrasonic cleaning for about 5 minutes. After stirring in a vessel, 3 g of this solution was dropped into a disposable plastic petri dish having an inner diameter of 54 mm and spread uniformly. This petri dish was dried for 1 day in a constant temperature room maintained at 37 ° C.

  After drying, the film formed from the petri dish was peeled off and stored for 1 day or more at normal pressure in a desiccator using diphosphorus pentoxide as a desiccant.

  About the obtained film, the thickness of the film was measured with the micrometer (CLM1-150QM by Mitutoyo Corporation, measuring force 0.5N). The thickness of the obtained film was 125 μm.

(Example 2)
A sodium alginate powder (manufactured by Nacalai Tesque Co., Ltd.) having a viscosity of 300 cps (1% aqueous solution) was dissolved in ion-exchanged water to prepare a concentration of 1.5%. To this aqueous solution, as a surfactant, polyoxyethylene sorbitan monostearate (TS-10MV manufactured by Nikko Chemicals Co., Ltd.) was added so that its concentration was 0.15%, and the base was obtained by stirring uniformly. An aqueous solution was obtained.

  A film was produced in the same manner as in Example 1 except that this base solution was used. The thickness of the obtained film was 116 μm.

Example 3
A sodium alginate powder (manufactured by Nacalai Tesque Co., Ltd.) having a viscosity of 300 cps (1% aqueous solution) was dissolved in ion-exchanged water to prepare a concentration of 1.5%. By adding polyoxyethylene lauryl ether (BL-4.2 manufactured by Nikko Chemicals Co., Ltd.) as a surfactant to this aqueous solution so that its concentration is 0.5%, and uniformly stirring the base, An aqueous solution was obtained.

  A film was produced in the same manner as in Example 1 except that this base solution was used. The thickness of the obtained film was 125 μm.

(Comparative Example 1: Control)
300 cps sodium alginate (manufactured by Nacalai Tesque) powder was dissolved in ion-exchanged water to prepare a concentration of 1.5%. A base aqueous solution was obtained without adding a surfactant to the aqueous solution.

  A film was produced in the same manner as in Example 1 except that this base solution was used. The thickness of the obtained film was 130 μm.

(Comparative Example 2)
A sodium alginate powder (manufactured by Nacalai Tesque Co., Ltd.) having a viscosity of 300 cps (1% aqueous solution) was dissolved in ion-exchanged water to prepare a concentration of 1.5%. By adding sorbitan monostearate (SS-10MV manufactured by Nikko Chemicals Co., Ltd.) as a surfactant to this aqueous solution, adjusting the concentration to 0.5%, and stirring uniformly, the base An aqueous solution was obtained.

  A film was produced in the same manner as in Example 1 except that this base solution was used. The thickness of the obtained film was 111 μm.

(Dissolution test of poorly soluble components from film (1))
One film prepared in Examples 1 to 3 and Comparative Examples 1 and 2 was placed on each plastic petri dish preheated to 37 ° C., 10 mL of physiological saline was added at 37 ° C., and a shaking incubator was added. And shaken at 300 rpm.

  0.3 mL of each sample was collected over time from the start of shaking, passed through a 0.45 μm filter, and 80 μL thereof was collected. To this was added 720 μL of methanol, stirred and subjected to centrifugation (10,000 rpm, 5 minutes), and the content (mg) of miconazole contained in the supernatant solution was determined by HPLC (manufactured by Shimadzu Corporation: LC-10AD). ). The conditions adopted for this HPLC were as follows.

  Using a Cosmo seal packed column (150 mm × 4.6 mm, manufactured by Nacalai Tesque, Inc.) with 10 mM potassium dihydrogen phosphate / acetonitrile (volume ratio 1: 4) as an eluent at room temperature and a flow rate of 0.8 mL / min. After separation, measurement was performed with UV detection (230 nm), and a retention time of about 7 minutes was obtained.

  The obtained results are shown in FIG. 1 and FIG.

  As shown in FIG. 1, it can be seen that the film produced in Example 1 eluted miconazole with time as compared with the film of Comparative Example 1. In particular, this elution occurred immediately from the beginning. When polyoxyethylene sorbitan monooleate was used as a surfactant, miconazole, which was conventionally poorly soluble, could be effectively eluted from the film. On the other hand, the film of Comparative Example 2 using a different one from the surfactant in the present invention showed poor dissolution of miconazole, which was almost the same as the result of Comparative Example 1 in which no surfactant was used.

  In addition, as shown in FIG. 2, in the surfactants (polyoxyethylene sorbitan monostearate and polyoxyethylene lauryl ether) used in Examples 2 and 3, miconazole was compared with the film of Comparative Example 1. It turns out that it eluted with time. In particular, these elutions occurred immediately from the start, and miconazole, which was conventionally poorly soluble, could be effectively eluted from the film.

  Thus, it turns out that the film produced in Examples 1-3 is useful as an oral film formulation which improved the solubility of the hardly soluble component.

(Examples 4 to 10 and Comparative Examples 3 to 9: Production and evaluation of film preparations using various poorly soluble components)
For Examples 4-10, each film-forming material described in Table 1 was used instead of sodium alginate powder, and each surfactant described in Table 1 was used instead of polyoxyethylene sorbitan monooleate. A solution shown in Table 1 was prepared in the same manner as in Example 1 except that an aqueous solution of the agent was prepared and each sparingly soluble component shown in Table 1 was added and dispersed in a predetermined content instead of miconazole. Was made.

  For Comparative Examples 3 to 9, a base aqueous solution was prepared using each film-forming material described in Table 1 instead of sodium alginate powder and without using a surfactant instead of polyoxyethylene sorbitan monooleate. A film shown in Table 1 was produced in the same manner as in Example 1 except that each sparingly soluble component shown in Table 1 was added and dispersed in a predetermined content instead of miconazole.

(Elution test for poorly soluble components from film (2))
Each of the films prepared in Examples 4 to 10 and Comparative Examples 3 to 9 was placed on each plastic petri dish previously heated to 37 ° C., 10 mL of physiological saline was added at 37 ° C., and shaken. The mixture was shaken at 300 rpm in an incubator.

  0.3 mL of each sample was collected over time from the start of shaking, passed through a 0.45 μm filter, and 80 μL thereof was collected. To this, 720 μL of methanol was added, stirred, and subjected to centrifugation (10,000 rpm, 5 minutes), and the content (mg) of each hardly soluble component contained in the supernatant solution was determined by HPLC (manufactured by Shimadzu Corporation: LC-10AD). The conditions adopted for each HPLC are shown in Table 2.

  Each of the films obtained in Examples 4 to 10 contained about 5 times (mg) or less of a poorly soluble component in about 10 minutes after the start of elution, as compared with those of Comparative Examples 3 to 9, respectively. Elution was confirmed. As described above, the film preparation of the present invention can be applied to various hardly soluble components.

  ADVANTAGE OF THE INVENTION According to this invention, the film formulation which improved the solubility of the hardly soluble component can be provided. Thus, for example, it can be used as an oral film preparation intended for intraoral application, and even a person who suffers from eating / deglutition disorder can easily take it. As a result, it is also useful as an oral application agent that reduces the burden on third parties such as nurses and caregivers. Furthermore, the film preparation of the present invention is not limited to such an oral use, but is used for transdermal uses such as patches (for example, wound dressings) and cosmetic sheets (for example, lotion pack sheets) (ie, for external use on the skin). It can also be used as a transdermal film formulation for use.

Claims (7)

A film formulation containing miconazole, a surfactant and a film-forming material,
The surfactant is at least one compound selected from the group consisting of polyoxyalkylene sugar fatty acid esters, polyoxyalkylene alkyl ethers and polyoxyalkylene ethers, and the film-forming material is alginic acid and its pharmaceuticals And at least one natural selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof, pullulan, pectin, dextran, gelatin, and chondroitin sulfate and pharmaceutically acceptable salts thereof A film preparation with improved miconazole solubility, which is a polysaccharide.   The film formulation of Claim 1 in which the said film forming material is contained in the ratio of 70 mass% to 95 mass% with respect to a film formulation.   The film formulation according to claim 1 or 2, wherein the surfactant is a polyoxyalkylene sugar fatty acid ester.   The film preparation according to claim 3, wherein the polyoxyalkylene sugar fatty acid ester is a polyoxyethylene sorbitan fatty acid ester.   The film formulation as described in any one of Claim 1 to 4 used for intraoral application.   The film preparation according to any one of claims 1 to 4, which is used for external use on the skin. Preparing a base solution comprising a film-forming material and a surfactant;
Dispersing miconazole in the base solution to obtain a casting solution;
Casting the casting solution onto a release film;
After drying, a step of cutting to a predetermined size together with a release film,
It has a door,
The surfactant is at least one compound selected from the group consisting of polyoxyalkylene sugar fatty acid esters, polyoxyalkylene alkyl ethers and polyoxyalkylene ethers;
The film-forming material comprises alginic acid and its pharmaceutically acceptable salt, hyaluronic acid and its pharmaceutically acceptable salt, pullulan, pectin, dextran, gelatin, and chondroitin sulfate and its pharmaceutically acceptable salt. At least one natural polysaccharide selected from the group consisting of:
A method for producing a film preparation with improved miconazole solubility.

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