JP2013103919A - Sustained release film preparation which contains chlorpheniramine maleate - Google Patents

Abstract

[PROBLEMS] To provide a film preparation which is excellent in sustained-release property of chlorpheniramine maleate and has a long-lasting medicinal effect.
A film preparation comprising chlorpheniramine maleate, a water-soluble film forming agent, and a carboxyvinyl polymer.
[Selection figure] None

Description

  The present invention relates to a film preparation containing chlorpheniramine maleate, and more particularly to a film preparation excellent in sustained-release property of chlorpheniramine maleate and having long-lasting drug efficacy.

  Chlorpheniramine maleate is known as one of histamine receptor antagonists and is widely used for suppressing itching and inflammation because of its pharmacological action. For example, it is included in general cold medicines and eye drops with antiallergic action for the purpose of preventing and treating sneezing and nasal congestion due to colds, eczema, urticaria, dermatitis, allergic symptoms and the like. Among them, most allergic eye drops that are commercially available contain chlorpheniramine maleate. However, those containing only chlorpheniramine maleate as an active ingredient are disadvantageous in that they are inexpensive but have a weak action and a poor sustainability. On the other hand, anti-allergic drugs other than chlorpheniramine maleate and steroids are used on the market, but it is not preferable from the viewpoint of economy and side effects.

Currently, liquid eye drops are the most widely used dosage forms for ophthalmic pharmaceutical preparations. In general, liquid eye drops are administered by dropping a suitable amount of eye drops onto the eyeball. The dropped ophthalmic solution is first stored in the conjunctival sac, then penetrates into the conjunctival epithelium or corneal epithelium and moves into the eye. The drug absorbed by the conjunctival epithelium further diffuses through the sclera and reaches the eye. The drug absorbed by the corneal epithelium first passes through the corneal stroma, reaches the anterior chamber, and further reaches the iris and the lens. Further, a part of the ciliary body reaches the ciliary body and further to the optic nerve head behind by the flow of aqueous humor flowing from the iris root to the ciliary stroma and further to the choroid behind (Non-patent Document 1).
Usually, the rate of transfer of eye drops into the cornea is less than a few percent of the total dose of the drug. In addition, since the corneal epithelium has a high affinity with a fat-soluble drug, the water-soluble drug has a reduced corneal permeability as compared with the fat-soluble drug. Therefore, an eye drop containing a water-soluble drug as an active ingredient has a low drug utilization rate. After instillation, most drugs that are not used are mixed with tears and lost outside the body, or from the punctum through the nasolacrimal duct to the nasal mucosa or pharyngeal mucosa where they are absorbed and enter the systemic circulation. It has been known.

Thus, in the case of liquid eye drops, particularly liquid eye drops containing a water-soluble drug such as chlorpheniramine maleate, most of the drugs are not used in the eye.
To overcome this problem, it may be possible to increase the drug concentration in liquid eye drops and enhance the intraocular transfer of the drug, but the high concentration of the drug is absorbed by the mucous membrane of the nose and throat through the nasolacrimal duct. However, when entering the systemic circulation, there is a risk that side effects may appear strongly.
In order to efficiently exert the efficacy of the drug in the eye, it is necessary to expose the drug to the target site at the target concentration for the target time. However, it is difficult to control this with normal liquid eye drops. In addition, liquid eye drops also have problems such as excessive eye drops, failure, and drug outflow due to blinking.

Therefore, in order to overcome the problems of these liquid eye drops, it has been proposed to make the eye drops into a gel, film or implant preparation.
For example, a water-soluble rebamipide-containing suspension hydrogel in which a high molecular weight hydroxypropylmethylcellulose or methylcellulose is added to eye drops to prevent the drug from flowing out of the eye or to prolong the efficacy (Patent Document 1) , Paclitaxel, a water-soluble film-forming polymer, and a fatty acid glyceride or fatty acid ester having a molecular weight of 150 to 4000, which is suitable for drug delivery to the eye (Patent Document 2). In order to maintain the drug concentration in the drug for a required period of time, an anti-inflammatory agent or a cytostatic agent is uniformly dispersed in the polylactic acid and molded into a short rod-like sustained release intraocular implant (Patent Document) 3) Carboxyvinyl polymer is blended as a gelling agent in normal eye drops, and dexamethasone dihydrogen dihydrogen phosphate Ophthalmic preparation (Patent Document 4) with improved durability of lithium, levofloxacin-containing thermogelled antibacterial aqueous pharmaceutical composition prepared by blending methylcellulose and polyethylene glycol into eye drops and gelling in the body after instillation (Patent Document 5) and the like have been reported.

Special table 2009-536940 JP-A-2005-533106 Japanese Patent Laid-Open No. 5-17370 JP-T-2001-518510 International Publication No. 2002/011734 Pamphlet

CLINICAN'96 No. 453 80-81

The film preparation is easy to administer, can reliably administer the drug to the affected area, and has a low risk of transferring the drug to another site, so it is preferable from the viewpoint of improving the drug utilization rate and reducing side effects It is. However, as a result of studies by the present inventors, when chlorpheniramine maleate is contained in a film preparation based on a water-soluble film-forming agent, chlorpheniramine maleate is released slowly, It was found that there is room for further improvement from the viewpoint of sustainability of medicinal effects.
In view of such circumstances, the present invention intends to provide a film preparation which is excellent in sustained release of chlorpheniramine maleate and has a long-lasting medicinal effect.

  As a result of intensive investigations on the above problems, the present inventor has shown that the film preparation contains a carboxyvinyl polymer, exhibits excellent sustained release properties, and contains chlorpheniramine maleate that lasts for a longer time. The present invention has been completed by finding that it can be made into a preparation.

  That is, the present invention provides a film preparation characterized by containing chlorpheniramine maleate, a water-soluble film forming agent, and a carboxyvinyl polymer.

  According to the film preparation of the present invention, sufficient sustained release is exhibited and the medicinal effect is maintained for a long time. Therefore, the pharmacological action of chlorpheniramine maleate can be effectively exhibited in the target affected area. For example, when the film preparation of the present invention is applied to the eye, it shows long-term effectiveness against itching, inflammation, conjunctivitis, etc. associated with hay fever and various allergic symptoms, rather than using normal liquid eye drops. .

It is a figure which shows the elution behavior of chlorpheniramine maleate in a film formulation. It is a figure which shows the durability of the antihistamine action of the chlorpheniramine maleate in the film formulation of Example 1. It is a figure which shows the durability of the antihistamine action of the chlorpheniramine maleate in the film formulation of the comparative example 1. It is a figure which shows the durability of the antihistamine action of the chlorpheniramine maleate in the liquid agent of the comparative example 2.

  The chlorpheniramine maleate used in the present invention is a compound represented by the name IUPAC as 3- (4-chlorophenyl) -N, N-dimethyl-3-pyridin-2-yl-propan-1-amine monomaleate. is there. Due to the stereochemical characteristics, there are d-form, l-form and dl-form, all of which are included in the present invention.

  Although content in particular of the chlorpheniramine maleate in the film formulation of this invention does not have a restriction | limiting, 0.1-10 mass% is preferable with respect to the formulation whole quantity, 0.3-10 mass% is more preferable, 0 More preferably, it is 6-7 mass%.

The water-soluble film-forming agent used in the present invention has a property of forming a hydrogel by being dissolved or viscous when contacted with water, or having a property of forming a film in a dry state. Is a molecule.
Examples of the water-soluble film forming agent include alginic acid such as sodium alginate or a salt thereof, pectin, carrageenan, xanthan gum, starch, tragacanth gum, xanthan gum, collagen, gelatin, galactomannan, glycoprotein, proteoglycan, glucosaminoglycan, polyvinyl Alcohol or a water-soluble cellulose derivative is exemplified.
Examples of the water-soluble cellulose derivative include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, or salts thereof.
As the water-soluble film forming agent used in the present invention, a water-soluble cellulose derivative is preferable from the viewpoint that a transparent and uniform film can be formed, and hydroxypropyl cellulose is more preferable.
These water-soluble film forming agents can be used alone or in combination of two or more.

Hydroxypropyl cellulose may be produced by a known method, or a commercially available product may be used. Examples of commercially available products include HPC-SSL, HPC-SL, HPC-L, HPC-M, HPC-H, and HPC-SFP (above, manufactured by Nippon Soda).
The degree of substitution in hydroxypropylcellulose is not particularly limited, and those having a desired degree of substitution can be obtained, but those containing 53 to 78% of hydroxypropoxyl groups are preferred. Further, the viscosity of hydroxypropylcellulose is not particularly limited, but for example, it is preferable that the kinematic viscosity (15th revised Japanese Pharmacopoeia) of a 2% aqueous solution at 20 ° C. is 1000 to 4000 mPa · s.

  Although there is no restriction | limiting in particular in content of the water-soluble film formation agent in the film formulation of this invention, 85-98.5 mass% is preferable with respect to the formulation whole quantity, 90-98.5 mass% is more preferable, 92. 5-97.5 mass% is further more preferable.

The carboxyvinyl polymer used in the present invention is a polymer mainly composed of acrylic acid.
Although there is no restriction | limiting in particular in the viscosity of a carboxy vinyl polymer, From the point of the persistent improvement of a medicinal effect, the thing whose kinematic viscosity of 0.2% aqueous solution in 20 degreeC is 4000-7500 mPa * s is preferable, for example.
The carboxyvinyl polymer may be produced by a known method, or a commercially available product may be used. Examples of commercially available products include Carbopol 980, Carbopol 981, ETD2050, Ultretz 10 (and above, NOVEON), Hibiswaco, Sinteral K, Sinteral L, and Sinteral M (and above, Wako Pure Chemical Industries).

  Although there is no restriction | limiting in particular in content of the carboxy vinyl polymer in the film formulation of this invention, 1 to 2.7 mass% is preferable with respect to the formulation whole quantity, and 1 to 2.7 mass% from the point of the durable improvement of a medicinal effect. More preferably, 1.3-2.3 mass% is further more preferable.

  The content ratio of the water-soluble film-forming agent to the carboxyvinyl polymer (water-soluble film-forming agent / carboxyvinyl polymer) in the film preparation of the present invention is preferably 28-98, preferably 33-98, from the viewpoint of improving the sustained efficacy. Is more preferable, and 40 to 75 is more preferable.

The film preparation of the present invention can be blended with other active ingredients other than chlorpheniramine maleate, if necessary, as long as the effects of the present invention are not impaired.
Other active ingredients include, for example, sodium cromoglycate, pranoprofen, tetrahydrozoline hydrochloride, dipotassium glycyrrhizinate, sodium chondroitin sulfate, sodium azulene sulfonate, potassium aspartate, magnesium aspartate, magnesium magnesium aspartate, vitamin B2 , Active vitamin B2, vitamin B6, panthenol, vitamin B12, vitamin E, taurine, neostigmine methyl sulfate, epsilon aminocaproate, naphazoline hydrochloride, allantoin, sulfamethoxazole, sulfamethoxazole sodium, ketotifen Examples thereof include fumarate and rebamipide.

In addition, the film preparation of the present invention is blended with optional components such as a pH adjuster, a stabilizer, a preservative, a surfactant, or a refreshing agent as necessary, as long as the effects of the present invention are not impaired. Can do.
Examples of the pH adjuster include hydrochloric acid, boric acid, citric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen phosphate, diphosphoric acid phosphate. Examples thereof include sodium hydrogen and potassium dihydrogen phosphate.

  Examples of the stabilizer include ascorbic acid, tocopherol acetate, tocopherol succinate, sodium bisulfite, benzoic acid, sodium benzoate, or sodium edetate.

  Examples of the preservative include cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, boric acid, or borax.

  Examples of the surfactant include polysorbate 80, polyoxyethylene hydrogenated castor oil, or polyethylene glycol monostearate.

  Examples of the refreshing agent include menthol, camphor, borneol, cinnamon oil and the like.

There is no restriction | limiting in particular in the manufacturing method of the film formulation of this invention, It can manufacture according to a well-known and usual manufacturing method. Specifically, the following production methods <Production method 1> to <Production method 4> can be mentioned, but are not limited thereto.
<Production method 1>
Chlorpheniramine maleate, a water-soluble film forming agent, a carboxyvinyl polymer, and, if necessary, optional components are uniformly mixed in an appropriate solvent to prepare a mixed solution for film preparation. This is spread with a coating machine, dried, and then cut into a desired shape and size to form a film preparation.

<Production method 2>
A silicon coat with holes formed on a flat plate such as glass is placed, and a mixed solution for film preparation prepared by the same procedure as in Production Method 1 is dropped into the holes and dried to obtain a film preparation.

<Manufacturing method 3>
A film preparation mixed solution prepared by the same procedure as in production method 1 is dropped onto a silicon coat frame placed on a flat plate such as glass, dried, and then cut out with a perforated punch of the desired size to obtain a film preparation. .

<Method 4>
An appropriate amount of the mixed solution for film preparation prepared by the same procedure as in Production Method 1 is weighed, dropped onto a flat plate such as glass and dried to obtain a film preparation.

  The solvent of the film preparation mixed solution in <Production Method 1> to <Production Method 4> is not particularly limited as long as it dissolves or uniformly disperses the components of the film preparation, and examples thereof include water, methyl alcohol, and ethyl alcohol. It is preferable to use propyl alcohol, isopropyl alcohol, or a mixture thereof.

  In the mixed solution for film preparation, the total concentration of chlorpheniramine maleate, water-soluble film forming agent and carboxyvinyl polymer is not particularly limited, but is 0.1 to the total amount of mixed solution for film preparation. 10 mass% is preferable, 0.3-8 mass% is more preferable, 0.5-6 mass% is further more preferable.

  Moreover, you may add the pH adjuster similar to the above to this mixed solution for film preparations. The pH (25 ° C.) of the mixed solution for film preparation is preferably 4.5 to 9.5, more preferably 5 to 9, and further preferably 5.5 to 8.5, from the viewpoint of improving the sustainability of the drug effect.

The film preparation of the present invention is used as a pharmaceutical preparation. Although the application site | part of a film formulation is not specifically limited, From the point by which the effect of this invention is exhibited effectively, applying to eyes is preferable.
When the film preparation of the present invention is used as an ophthalmic film preparation, eyestrain, blurred eyes (when there are many in the eyes), itchy eyes, redness of the eyes (conjunctival redness, etc.), blepharitis (eyelid sore) ), Nasty eyes, sty, conjunctivitis (blurred eyes), ophthalmitis due to ultraviolet rays or other rays (snow eyes, etc.), eye disease prevention (when swimming, dust or sweat enters the eyes, etc.), hard contact lenses It can be preferably applied to the improvement of unpleasant feeling when worn or the improvement of a foreign object feeling (feeling of rolling).

The thickness of the film preparation of the present invention and the area and shape of one sheet are not particularly limited, but when used as an ophthalmic film preparation, a film having a thickness of 0.01 mm to 0.5 mm is finally obtained. it is preferred to preferred to the area of one Atari to 20mm ² ~35mm ^2. As the shape, for example, a square, a rectangle, a rhombus, an ellipse, a circle, a semicircle, or a crescent shape can be adopted.

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

Example 1
Mixing 90 g of methanol with 0.135 g of chlorpheniramine maleate, 4.0 g of hydroxypropyl cellulose (HPC-H, Nippon Soda Co., Ltd.) and 0.075 g of carboxyvinyl polymer (Carbopol 981, BF Goodrich) And stirred until uniform. Next, while stirring this mixed solution, an appropriate amount of sodium hydroxide was added to adjust the pH to 8.0, and methanol was further added to bring the total amount to 100 g to obtain a mixed solution for film preparation.
The obtained mixed solution for film preparation was dropped by 75 μL onto a slide glass using a micropipette, dried at 40 ° C. for 2 hours, and then the film preparation of the present invention (average drug content: 0.0764 mg / sheet, n = 10, RSD = 0.7%).

Comparative Example 1
In 90 g of methanol, 0.135 g of chlorpheniramine maleate and 4.0 g of hydroxypropylcellulose (HPC-H, Nippon Soda Co., Ltd.) were mixed and stirred until uniform. Furthermore, methanol was added with stirring to make the total amount 100 g, to obtain a mixed solution for film preparation.
The obtained mixed solution for film preparation was dropped by 75 μL onto a glass slide using a micropipette, dried at 40 ° C. for 2 hours, and then film preparation (average drug content: 0.0743 mg / sheet, n = 10, R.P. SD = 1.1%).

Comparative Example 2
In 90 g of purified water, 0.03 g of chlorpheniramine maleate was mixed and stirred until uniform. Further, purified water was added with stirring to make a total volume of 100 mL, and a solution was obtained as an aqueous solution containing 0.03% chlorpheniramine maleate.

Test Example 1 (Drug elution evaluation: In vitro)
The film preparation obtained in Example 1 and Comparative Example 1 was subjected to a dissolution test. The test was conducted according to the dissolution test (flow-through cell method) described in the 15th revised Japanese Pharmacopoeia, and the test solution was purified water at 37 ° C. and a flow rate of 4 mL / min.
From FIG. 1, it takes 30 minutes for 100% of the drug to be dissolved even in the film preparation of Comparative Example 1 in which no carboxyvinyl polymer is blended, and when an in vivo test is assumed, the supply of the drug is higher than that of normal eye drops. The possibility of sustained release was suggested. On the other hand, the film preparation of Example 1 containing a carboxyvinyl polymer showed a more sustained release pattern, and it took 120 minutes for 100% of the drug to elute.
Therefore, it was shown that the combination of carboxyvinyl polymer is effective for sustained release of chlorpheniramine maleate.

Test Example 2 (Histamine vascular permeability enhancement inhibitory evaluation: In vivo)
The film preparation obtained in Example 1 was cut into small pieces so that the dose of chlorpheniramine maleate was 0.03 mg / sheet, and this was cut into the right eye (treated eye) of a guinea pig (4 weeks old, Hartley male). 10 μL of purified water was administered to the left eye (control eye). After a certain time (30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours) after administration, 10 mL of 1% histamine aqueous solution was administered to both eyes, and immediately, the Evans blue solution was adjusted to 50 mg / kg. Administered intravenously. After 30 minutes, the blood was lethal and the left and right eye conjunctival tissues were collected. The collected tissue pieces were each left overnight in a 1M aqueous potassium hydroxide solution at 35 ° C., added with 1.5 mL of 0.2M aqueous phosphoric acid solution and 4.5 mL of acetone, shaken for 15 minutes, Centrifugation was performed at 3000 rpm for 15 minutes, and the absorbance of the supernatant was measured at a wavelength of 620 nm.
Evaluation of the film preparation of Comparative Example 1 was performed in the same procedure as in Example 1 except that the film preparation of Comparative Example 1 was used for the treated eye.
Evaluation of the liquid preparation of Comparative Example 2 was performed in the same procedure as Example 1 except that 10 μL of 0.03% chlorpheniramine maleate-containing aqueous solution was administered to the treated eye.
In this test, when chlorpheniramine maleate suppresses the action of instilled histamine, the blood vessel permeability of the dye is suppressed, and the measured value of absorbance becomes low. That is, when the absorbance is low, it can be determined that the pharmacological effect is exerted.
Specifically, guinea pigs shed blue tears when the absorbance was 1.4 or higher, and blue lips did not shed when the absorbance was 0.7 to 1.4, but the conjunctiva of the guinea pigs was blue and dim. From this, when the absorbance was about 0.7 or less, it was judged that the antihistamine effect by chlorpheniramine maleate was exhibited.

  From the results shown in FIGS. 2 (a) to 2 (c), the administration of the liquid preparation of Comparative Example 2 had a duration of medicinal effect up to 2 hours after instillation, and the duration of medicinal efficacy was the shortest. The film preparation of Comparative Example 1 lasted up to 4 hours after administration, and the effect of the film preparation as a device was confirmed. In the film preparation of Example 1 in which the carboxyvinyl polymer was blended, the duration of the drug effect was shown to be 6 hours or more, and the usefulness of blending the carboxyvinyl polymer was demonstrated. In addition, since there was a correlation between the results between the in vivo test and the in vitro test, chlorpheniramine maleate gradually moved to the affected area and acted to improve the sustainability of the drug effect. It was suggested that

Claims (5)

  A film preparation comprising chlorpheniramine maleate, a water-soluble film forming agent and a carboxyvinyl polymer.   The film preparation according to claim 1, wherein the water-soluble film forming agent is a water-soluble cellulose derivative.   The film preparation according to claim 2, wherein the water-soluble cellulose derivative is one or more selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and salts thereof.   The film preparation according to any one of claims 1 to 3, which is an ophthalmic film preparation.   A method for gradual release of chlorpheniramine maleate in a film preparation, comprising containing a carboxyvinyl polymer in a film preparation containing chlorpheniramine maleate and a water-soluble film forming agent.

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