JP4867128B2 - Oral rhinitis treatment composition - Google Patents

Description

The present invention relates to a composition for treating oral rhinitis that is taken twice a day and contains pseudoephedrine and ketotifen fumarate.

  Allergic rhinitis is rhinitis ("Kojien" 5th edition) whose main symptoms are nasal obstruction due to frequent sneezing, secretion of large amounts of watery nasal discharge, and edematous thickening of the nasal mucosa. Symptoms such as sneezing, nasal discharge, and nasal congestion listed here cause headaches, decreased concentration, etc., and are a heavy burden in daily life. The number of patients with allergic rhinitis caused by hay fever typified by cedar and cypress, house dust, mites and the like has been increasing in recent years, and development of a drug that effectively and safely suppresses these symptoms is desired.

  Drugs used for allergic rhinitis include antihistamines, antiallergic drugs, vasoconstrictor drugs, and anticholinergic drugs. Of these, antiallergic drugs such as mequitazine and ketotifen fumarate are taken twice a day because of their sustained action. On the other hand, nasal congestion (nasal congestion) is the main sign of allergic rhinitis, and vasoconstrictors that improve nasal congestion are often used in combination. However, vasoconstrictors that are used in combination, such as pseudoephedrine and phenylpropanolamine hydrochloride, are often effective but have a short duration, and are generally taken three times a day. Thus, if the usage of the concomitant drug is different, it cannot be expected to contribute to compliance as a whole prescription.

  By the way, in the field of over-the-counter drugs, a combination drug containing a plurality of active ingredients is the mainstream. In the case of a combination drug, since multiple active ingredients are included, many symptoms can be efficiently suppressed with a single dose, and the concomitant drugs are included in the same formulation, so compliance Improvement can be expected.

  As for compliance, many people feel painful to take drugs such as tablets and capsules, and it is preferable to take less. Also, if the number of doses decreases, forgetting to drink can be prevented. On the other hand, many of the over-the-counter drugs for rhinitis are taken three times a day, but it is considered more beneficial to take less frequently.

  When administered orally, the drug is absorbed through the intestinal tract and distributed throughout the body through the blood. If the blood concentration of the drug at this time is within a certain range, the drug effect is recognized. This is called effective blood concentration. If this effective blood concentration can be maintained for a long time with a single dose, the number of doses can be reduced, leading to improved compliance.

  In addition, over-the-counter drugs can be purchased by pharmacies without a doctor's prescription, and safety is particularly important. If the blood concentration of the drug exceeds the effective blood concentration, side effects may occur. Therefore, a means for adjusting the blood concentration of the drug is effective by subjecting the drug to sustained release, adjusting the dissolution of the drug, and adjusting the amount of the drug absorbed in the intestine.

  Therefore, the present inventors, as a composition for the treatment of oral rhinitis that suppresses symptoms of allergic rhinitis, blends pseudoephedrine with ketotifen fumarate, which is an antiallergic agent, and controls the release of pseudoephedrine to achieve high safety and The present inventors have found a composition for treating oral rhinitis that is expected to be effective twice a day.

Until now, tablets with sustained release of only pseudoephedrine hydrochloride have been disclosed (Patent Document 1). Moreover, although the chemical | medical agent which mix | blended ketotifen fumarate and pseudoephedrine hydrochloride is disclosed (patent document 2), this drug does not release pseudoephedrine hydrochloride gradually.
JP-A-11-228391 JP 2002-332229 A

  An object of the present invention is to provide a composition for treating oral rhinitis that is highly compliant and ensures safety and effectiveness.

  As a result of investigations by the present inventors, it was found that a composition for treating oral rhinitis that is administered twice a day and contains pseudoephedrine and ketotifen fumarate and controlled to release pseudoephedrine or a salt thereof can achieve the above-mentioned object. The present invention has been completed.

  According to the present invention, a composition for treating oral rhinitis with high compliance and safety and effectiveness is ensured by blending pseudoephedrine and ketotifen fumarate and maintaining the effective blood concentration for a long time by gradually releasing pseudoephedrine. It became possible to provide.

  Pseudoephedrine is a drug that acts directly on α-adrenergic receptors and causes vasoconstriction. As a result, it is a drug that acts on the mucosal tissue of the nose that is expanded or edema caused by rhinitis, contracts the expansion of the mucosal tissue, reduces edema, and suppresses nasal congestion. As a normal usage, it is taken three times a day due to the nature of this drug.

  The dose of pseudoephedrine in the product of the present invention is 80 to 90 mg at a time for an adult as hydrochloride, and 160 to 180 mg as a daily dose.

  The pseudoephedrine of the present invention is subjected to sustained release. As a method for sustained release, a general sustained release technique can be used. Specifically, there are a method of coating pseudoephedrine with an excipient and a method of gradually releasing it into a matrix with wax or polymer.

  Pseudoephedrine exists in the form of hydrochloride or sulfate. Either can be used in the present invention.

  Ketotifen fumarate has a chemical mediator-based anti-anaphylaxis and anti-histamine action, and reduces hypersensitivity of the respiratory tract, nasal mucosa, etc. (Zaziten package insert). Due to this pharmacological action, it is used to treat symptoms such as allergic rhinitis, bronchial asthma, eczema and dermatitis.

  The dose of ketotifen fumarate in the present invention is 1.38 mg or less (1 mg or less as ketotifen) at a time.

  The product of the present invention can contain other medicinal components other than pseudoephedrine and ketotifen fumarate. Such medicinal ingredients include anticholinergic agents such as belladonna total alkaloids and isopropamide iodide, anti-inflammatory agents such as lysozyme chloride and serrapeptidase, central nervous stimulants such as caffeine and anhydrous caffeine, licorice, ginger, carrots, etc. Herbal medicines or herbal extracts, vitamins such as vitamin B and vitamin C, and the like.

  In addition to this, the additive normally used for manufacture of a solid formulation can be used in the range which does not impair the effect of this invention. For example, excipients, disintegrants, binders, lubricants, lipids, surfactants, sweeteners, flavoring agents, fragrances and the like can be mentioned.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited to these Examples and the like.
Example 1
(Prescription)
(Slow release part)
90g pseudoephedrine hydrochloride
Hydroxypropyl methylcellulose 500g
6.4g of light anhydrous silicic acid
Magnesium stearate 3.2g
Talc 4g
(Quick release part)
90g pseudoephedrine hydrochloride
Ketotifen fumarate 2.76 g
Lactose 547.1g
48g of crystalline cellulose
Hydroxypropylcellulose 28g
Low substituted hydroxypropylcellulose 48g
5.6g light silicic anhydride
Each component and amount of the sustained release part were weighed, mixed after sieving to obtain granules before tableting of the sustained release part. In addition, each component and the amount in the quick release part were weighed, mixed and pulverized, and the mixed powder was granulated with a high speed stirring granulator using purified water as a granulating solvent. The granulated product obtained after drying is sieved, and the sieved product is crushed and added to the sieved product. Further, 4 g of magnesium stearate and 40 g of low-substituted hydroxypropylcellulose are added and mixed, and granule before immediate release part tableting Got. Tableting was performed using the granule before sustained release part granulation and the granule before immediate release part tableting, and a double-layer tablet (weight ratio 1: 1 of sustained release part / fast release part) of 1 tablet weight (twice a day, 2 tablets once). In addition, as for the hydroxypropyl methylcellulose, Metrows 60SH4000 (manufactured by Shin-Etsu Chemical Co., Ltd.) is used.

Example 2
(Prescription)
(Slow release part)
90g pseudoephedrine hydrochloride
Beradonna total alkaloid 0.3g
Hydroxypropyl methylcellulose 712 g
6.4g of light anhydrous silicic acid
Magnesium stearate 3.2g
Talc 4.0g
(Quick release part)
90g pseudoephedrine hydrochloride
Ketotifen fumarate 2.76 g
Belladonna Total Alkaloid 0.3g
100g anhydrous caffeine
Lactose 451g
48g of crystalline cellulose
Hydroxypropylcellulose 28g
Low substituted hydroxypropylcellulose 48g
5.6g light silicic anhydride
Each component and amount of the sustained release part were weighed, mixed after sieving to obtain granules before tableting of the sustained release part. In addition, each component and the amount in the quick release part were weighed, mixed and pulverized, and the mixed powder was granulated with a high-speed stirring granulator using purified water as a granulating solvent. The granulated product obtained after drying is sieved, and the sieved product is crushed and added to the sieved product. Further, 4 g of magnesium stearate and 40 g of low-substituted hydroxypropylcellulose are added and mixed, and granule before immediate release part tableting Got. Tableting was performed using the granule before sustained release part granulation and the granule before immediate release part tableting, and a double-layer tablet (weight ratio 1: 1 of sustained release part / fast release part) of 1 tablet weight (twice a day, 2 tablets once). In addition, as for the hydroxypropyl methylcellulose, Metrows 60SH4000 (manufactured by Shin-Etsu Chemical Co., Ltd.) is used.

Example 3
(Prescription)
(Slow release part)
(Elementary granules)
108g pseudoephedrine hydrochloride
Belladonna Total Alkaloid 0.36g
80g ethyl cellulose
Selfia CP-203 108g
(coating)
Ethylcellulose 88.9g
Triethyl citrate 4.45g
(Quick release part)
72g pseudoephedrine hydrochloride
Ketotifen fumarate 2.76 g
Belladonna total alkaloid 0.24g
100g anhydrous caffeine
Lactose 297g
Cornstarch 180g
Calcium hydrogen phosphate 200g
Mannitol 100g
Crystalline cellulose 64g
Hydroxypropylcellulose 42g
Low substituted hydroxypropylcellulose 112g
Light anhydrous silicic acid 9g
The above amounts of pseudoephedrine hydrochloride and belladonna total alkaloids were dissolved in 95% ethanol, and then ethylcellulose was dissolved. This solution was laminated on the core particles using a bottom spray type fluidized bed coating machine to form sustained-release elementary granules. Separately, the above amounts of ethyl cellulose and triethyl citrate were dissolved in 95% ethanol. This solution was laminated on the sustained-release elementary granules using GPCG-1 to obtain sustained-release granules. In addition, each component and amount of the quick release part are weighed, mixed and pulverized, and the mixed powder is granulated with a fluidized bed granulation dryer using a purified water / ethanol (1: 1) mixture as a granulating solvent. Dried. The obtained granulated product was sieved, and the sieved product was roughly crushed and then added to the sieved product and mixed to obtain immediate-release granules. To sustained release granules and immediate release granules, 90 g of croscarmellose sodium and 8 g of magnesium stearate were added, mixed and tableted, and 1 tablet weight 406 mg (sustained release part / fast release part weight ratio 3: 2) Multiple unit type tablets (taken 2 tablets twice a day once) were obtained.

Comparative Example 1
Pseudoephedrine hydrochloride 60 mg tablets (3 times a day, 1 tablet once) were prepared as follows and subjected to the test.
(Prescription)
180g pseudoephedrine hydrochloride
Lactose 1271.1g
90g of crystalline cellulose
Hydroxypropylcellulose 60g
Low substituted hydroxypropylcellulose 180g
Light anhydrous silicic acid 12.6g
The mixed powder obtained after weighing and mixing the above components and quantities was granulated with a high-speed agitation granulator using purified water as a granulating solvent. The granulated product obtained after drying was added with 9 g of magnesium stearate, mixed and tableted to obtain an uncoated tablet having a tablet weight of 300 mg.

Comparative Example 2
(Prescription)
180g pseudoephedrine hydrochloride
Ketotifen fumarate 2.76 g
Lactose 1255.5g
48g of crystalline cellulose
Hydroxypropylcellulose 28g
Low substituted hydroxypropylcellulose 88g
Light anhydrous silicic acid 12g
The mixed powder obtained after weighing and mixing the above components and quantities was granulated with a high-speed agitation granulator using purified water as a granulating solvent. To the granulated product obtained after drying, 7.2 g of magnesium stearate and 4 g of talc were added and mixed and tableted to obtain an uncoated tablet having a tablet weight of 406 mg (twice a day, 2 tablets once a day). .

Comparative Example 3
(Prescription)
120g pseudoephedrine hydrochloride
Ketotifen fumarate 2.76 g
Belladonna Total Alkaloid 0.4g
100g anhydrous caffeine
Lactose 1215.1g
48g of crystalline cellulose
Hydroxypropylcellulose 28g
Low substituted hydroxypropylcellulose 88g
Light anhydrous silicic acid 12g
The mixed powder obtained after weighing and mixing the above components and quantities was granulated with a high-speed agitation granulator using purified water as a granulating solvent. To the granulated product obtained after drying, 7.2 g of magnesium stearate and 4 g of talc were added and mixed and tableted to obtain an uncoated tablet having a tablet weight of 406 mg (twice a day, 2 tablets once a day). .

Test Example About the tablets obtained in Example 2 and Comparative Examples 1 to 3, a dissolution test of pseudoephedrine hydrochloride (JP paddle method, paddle rotation speed: 50 rpm, test solution: purified water) is shown in FIG. An elution curve was obtained.
In addition, ketotifen fumarate capsules (Zazidene 1 mg capsule, ketotifen fumarate 1.38 mg / capsule, hereinafter referred to as “commercially available product”), tablets obtained in Example 2 and Comparative Examples 2 and 3, elution of ketotifen fumarate As a result of carrying out the test (Japanese JP paddle method, paddle rotation speed: 50 rpm, test solution: purified water), an elution curve shown in FIG. 2 was obtained.

  Next, based on the elution curves shown in FIGS. 1 and 2, blood concentrations of pseudoephedrine hydrochloride and ketotifen fumarate were predicted by simulation. The results of blood concentration transition simulations of both drugs in Comparative Example 1 + commercially available product, Comparative Example 2, Comparative Example 3 and Example 2 when taken at prescribed dosages are shown in FIGS.

  Comparative Example 1 + commercial product had no particular problem from the viewpoint of effective blood concentration (FIG. 3). However, Comparative Example 1 is a type that is taken three times a day, and a commercial product is a type that is taken twice a day. Since the time taken for pseudoephedrine and ketotifen fumarate is different, as a result, the number of times taken per day is increased. It was confirmed that the drug compliance may be inappropriate.

  In Comparative Example 2, since the blood concentration of pseudoephedrine hydrochloride immediately after taking was too high, it was confirmed that it was difficult to obtain an appropriate effect due to the risk of side effects (FIG. 4). In Comparative Example 3, since the effective blood concentration of pseudoephedrine hydrochloride could not be maintained for a long time, it was confirmed that the effect on the continuous improvement of nasal symptoms may be insufficient (FIG. 5). On the other hand, in Example 2 according to the present invention, it is excellent in compliance when taken twice a day, and since the effective blood concentrations of ketotifen fumarate and pseudoephedrine hydrochloride are maintained long, nasal symptoms can be continuously improved. This was confirmed (FIG. 6).

  According to the present invention, sufficient efficacy and safety can be ensured by taking twice a day in a rhinitis drug containing pseudoephedrine and ketotifen fumarate. Therefore, a rhinitis drug with high compliance can be provided.

The result of having carried out the elution test of the pseudoephedrine hydrochloride (the JP paddle method, a paddle rotation speed: 50 rpm, a test liquid: purified water) about the tablet obtained in Example 2 and Comparative Examples 1-3 is shown. The results of conducting a ketotifen fumarate dissolution test (Japanese puddled paddle method, paddle rotation speed: 50 rpm, test solution: purified water) on the commercially available products, the tablets obtained in Comparative Example 2, Comparative Example 3 and Example 2 It is shown. Comparative Example 1 + simulated blood concentrations of pseudoephedrine hydrochloride and ketotifen fumarate when taking commercially available products. It is a simulation of blood concentrations of pseudoephedrine hydrochloride and ketotifen fumarate when taking Comparative Example 2. It is a simulation of blood concentrations of pseudoephedrine hydrochloride and ketotifen fumarate when taking Comparative Example 3. It is a simulation of blood concentrations of pseudoephedrine hydrochloride and ketotifen fumarate when Example 2 is taken.

Claims (1)

A sustained release granule layer containing pseudoephedrine hydrochloride and hydroxypropylmethylcellulose and not containing low-substituted hydroxypropylcellulose, and containing pseudoephedrine hydrochloride, ketotifen fumarate and low-substituted hydroxypropylcellulose, and hydroxypropylmethylcellulose A composition for treating oral rhinitis, which is a bilayer tablet comprising an immediate-release part granule layer not contained.

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