JP4630614B2 - Fast disintegrating solid preparation - Google Patents

Description

  The present invention relates to a rapidly disintegrating solid preparation.

  In recent years, it has been desired to develop a tablet that can be taken without water as a dosage form considering the ease of taking by consumers. Usually, when taking solid preparations such as tablets, water is required, and there is a problem that it is not convenient. In addition, there is a problem that it is difficult to take a large tablet or a tablet with a large dose. In particular, patients who have difficulty swallowing, children, and elderly people may suffocate by using the throat. On the other hand, chewable tablets do not require water, but the chewing ability is not suitable for children and elderly people with weak teeth. In order to solve these problems, there are dosage forms that disintegrate rapidly in the oral cavity.

As a prior art, as a conventional patent relating to a rapidly disintegrating preparation, there are those relating to a rapidly disintegrating preparation containing erythritol or mannitol (Patent Document 1 and Patent Document 2). Patent Document 1 relates to a compressed composition imparted with fast disintegration by blending erythritol, and Patent Document 2 relates to a preparation imparted with rapid disintegration by blending mannitol. However, erythritol and mannitol have poor moldability and require many excipients for formulation.
There is also a patent relating to a solid pharmaceutical preparation (Patent Document 3). Patent document 3 gives quick disintegration by blending erythritol, crystalline cellulose, and a disintegrant into a pharmaceutical ingredient, but the disintegrant to be used is crospovidone which is a pharmaceutical additive. I can not use it.

There exists patent document 4 as a patent which provided quick disintegration by making a tablet porous. In Patent Document 4, sugar alcohol and starch are kneaded into an infiltrated lump, then rolled and molded, and further dried under reduced pressure to make it porous and impart quick disintegration. However, since the manufacturing method is complicated and a special apparatus is required, the manufacturing method is inferior in versatility.
Patents that devise the manufacturing method include Patent Document 5. Patent Document 5 imparts quick disintegration by adding water to a medicinal ingredient and a saccharide and moistening, compressing the wet powder, and then drying. However, there is a problem that it is difficult to use for an active ingredient that deteriorates when coexisting with water, and a special device for drying wet tablets is required.
Therefore, it is necessary to develop a solid preparation excellent in disintegration without requiring complicated processes and special production equipment.

International Publication Number WO98 / 02185 JP 2001-58944 A Japanese Patent Laid-Open No. 10-182436 JP 2003-137815 A Japanese Patent No. 3069458

  An object of this invention is to provide the solid formulation which disintegrates rapidly, when it puts in an intraoral area, without requiring a complicated process and special manufacturing equipment.

  As a result of intensive studies to solve these problems, the inventors of the present invention can obtain a rapidly disintegrating solid preparation that rapidly disintegrates when put into the oral cavity when a mixed powder containing DFA III is tableted. And found the present invention.

That is, the main configuration of the present invention is as follows.
(1) As an excipient, sugar alcohol, starches and crystalline celluloses are included,
Free of sucrose, reduced maltose and lactose,
3 to 70% by mass of difructose anhydride III (hereinafter referred to as “DFA III”) , which is a rapidly disintegrating component of a solid preparation that disintegrates and exhibits functionality ,
A rapidly disintegrating tablet that disintegrates or dissolves within 180 seconds in the oral cavity.
(2) minerals, vitamins, rapidly disintegrating tablet preparation according to, characterized in that it comprises one or more kinds selected from plant extracts, (1).
(3) rapidly disintegrating tablet preparation according to the particle diameter of DFAIII is characterized in that at 500μm or less (1) or (2).

  According to the present invention, a rapidly disintegrating solid preparation having an extremely excellent disintegrating property can be easily produced by a widely used method without using a special apparatus / production method.

The present invention is described in detail below.
The fast disintegrating solid preparation referred to in the present invention is a solid preparation that rapidly disintegrates when placed in the oral cavity.

  Difructose anhydride (DFA) is a reducing disaccharide in which the reducing ends of two fructose are bonded to a hydroxyl group other than one reducing end. Traditionally known to exist in caramel etc., but industrially fermented inulin with inulin-degrading enzymes such as inulin fructotransferase (EC2.4.1.93) produced by Arthrobacter sp. Strain H65-7. Or levan can be fermented with levanfructotransferase (EC2.4.1.10) produced by Arthrobacter nicotinvorans GS-9. There are five types of derivatives due to the difference in the binding mode of two molecules of fructose, which are referred to as DFAI, DFAII, DFAIII, DFAIV, and DFAV, respectively. In the present invention, DFAIII (α-D-fructofuranose-β-D-fructofuranose-2 ', 1: 2,3'-dianhydride), which has excellent industrial production efficiency and stability after production, is used. To do.

Examples of the excipient used in the present invention include carbohydrates, starches, and celluloses.
Examples of the saccharides include all commercially available products such as sucrose, lactose, maltose, glucose, trehalose, reduced lactose, reduced maltose, sorbitol, mannitol, xylitol.

Starches include corn starch, wheat starch, rice starch, potato starch, pregelatinized starch, partially pregelatinized starch, tapioca starch, high amylose starch, hydroxypropyl starch, starch hydrolysate, acetate starch, phosphate starch, octenyl succinate Examples include all commercially available products such as acid starch, carboxymethyl starch, phosphoric acid crosslinked starch, oxidized starch, dialdehyde starch, acid-treated starch and sodium hypochlorite-treated starch.
Examples of celluloses include all commercially available products such as crystalline cellulose, powdered cellulose, carboxymethylcellulose calcium, and sodium carboxymethylcellulose.
These excipients can be used alone or in combination of two or more.

As a compounding quantity of DFAIII, 1-80 mass%, Preferably it is 2-75 mass%, Most preferably, 3-70 mass% is desirable. If the blending amount of DFAIII deviates from this range, tableting troubles such as capping and sticking occur again during tableting, and the disintegration time is delayed, so the above range is desirable.
In the present invention, minerals, vitamins, plant extracts and the like can be contained in the solid preparation as active ingredients.

  Minerals, for example, calcined calcium such as dolomite, eggshell calcium, scallop shell calcium, oyster shell calcium, salmon calcium, sea urchin shell calcium, fossilized seaweed calcium, pearl calcium, beef bone calcium, fish bone powder calcium, fish scale calcium, Or high natural calcium content such as uncalcined calcium, or calcium materials such as calcium carbonate, calcium phosphate, calcium lactate, calcium gluconate, calcium citrate, calcium chloride, etc., magnesium chloride, magnesium carbonate, magnesium sulfate Magnesium materials such as heme iron, iron pyrophosphate, iron gluconate, iron iron citrate, iron materials such as iron chloride, iron lactate, iron oxide, iron sulfate, zinc materials such as zinc gluconate and zinc sulfate, gluconic acid Examples include copper materials such as copper sulfate, high iodine content materials such as seaweed powder, and other mineral yeasts that are high in minerals such as magnesium, iron, zinc, copper, chromium, selenium, manganese, molybdenum, and iodine. And all available commercial products can be used.

  Vitamins include vitamin A such as retinol, carotenoid compounds such as palm oil carotene, Dunaliella carotene and lycopene, vitamin B1 such as thiamine hydrochloride and thiamine nitrate, vitamin B2 such as riboflavin, pyridoxine hydrochloride and phosphate Vitamin B6 such as pyridoxal, vitamin B12 such as cyanocobalamin, pantothenic acids such as calcium pantothenate and sodium pantothenate, vitamin Ps such as methyl hesperidin, hesperidin, rutin, folic acid, biotin, ascorbic acid and ascorbic acid Vitamin C such as sodium, vitamin D such as vitamin D2, vitamin D3, vitamin E such as d-α-tocopherol, d-β-tocopherol, d-γ tocopherol, vitamin K2, etc. Use all commercially available products Can.

Specific examples of plant extracts include mulberry leaves, banaba, isoflavones, cranberries, turmeric, catechin, ginseng leaves, ginkgo biloba leaves, elephants, St. John's wort, echinacea, perilla seeds, perilla leaves, black cohosh, Maca, Ume, Blueberry, Saw Palmetto, Pumpkin Seeds, Maria Thistle, Gymnema Sylvestre, Strawberry Tea, Rooibos Tea, Barley, Merirot, Pueraria Mirifica, Chest Tree, Pomegranate Seeds, Garcinia, Citrus Aurantium, Clove, Centella Asia Chica, Grape Seeds, Red wine extract, millet, horsetail, agaricus mushroom, maitake, garlic, kidachi aloe, propolis, buckwheat young leaves, black potato moromi vinegar, elder, white willow, hops, chamomile, oats, guarana, ashwagan , Kola, Ibright, Asparagus chemos, Sage, Ginger, Cats claw, Valerian, Rice germ, Pepper, Barley young leaf, Tomato, Onion, Basil, Kale, Ashitaba, Rosemary, Thyme, Broccoli, Parsley, Ayamurasaki, Celery, protein, ginseng, etc. These powder extracts are obtained by separating and concentrating pulverized products such as fruits, seeds and leaves, or extracts extracted from fruits, seeds, leaves and the like with an aqueous ethanol solution and, if necessary, adding additives such as excipients. It can be obtained by drying and commercially available products can be used regardless of the production method.
The particle diameter of DFA III is 500 μm or less, preferably 400 μm or less, particularly preferably 300 μm or less. When the particle size is large, roughness occurs in the oral cavity. Further, segregation occurs during production, resulting in a preparation lacking in content uniformity.

The solid dosage form of the present invention is preferably a tablet or granule.
Moreover, the following inactive components can also be contained in order to improve manufacturability. Inactive ingredients in the present invention include dextrin, guar gum, xanthan gum, sodium alginate, gum arabic, guar gum enzymatic degradation product, tragacanth gum, pullulan, carrageenan, agar, gelatin, soy dietary fiber, methylcellulose, low-substituted hydroxypropylcellulose, hydroxy All commercially available products such as propyl starch, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, vegetable hardened oil, vegetable oil powder, carnauba wax, cacao oil powder, sucrose fatty acid ester, magnesium stearate, talc, etc. Can be mentioned.
Furthermore, fruit juice powder, a fragrance | flavor, etc. can be mix | blended for the purpose of improving seasoning and flavor as needed.
The tablet of the present invention is not affected by its shape and weight, and these are produced according to a general production method.

  The rapidly disintegrating solid preparation of the present invention is prepared by, for example, adding DFA III as it is or evenly mixed with carbohydrates, starches, celluloses, active ingredients and the like into granules by an appropriate method, and then according to a conventional method. It can be manufactured by compression molding. At this time, the inert component may be added. Alternatively, it can be produced by adding carbohydrates, starches, celluloses, and active ingredients to DFA III, and directly compressing and producing a mixture in which the inactive ingredients are evenly mixed.

The pressure at the time of compression molding may be arbitrarily set from the disintegration property in the oral cavity and the hardness of the tablet, but the oral disintegration time is sufficient even if the present invention is used to have physical properties that can withstand distribution. It doesn't have to be greatly damaged. Thus, the molding pressure and tablet hardness can be a conventional tablet comparable, compacting pressure 100~4000kg / cm ^2, preferably 100~3500kg / cm ^2, particularly preferably from 100~3000kg / cm ^2, tablet hardness Is 1 to 15 kgf, preferably 1 to 13 kgf, and particularly preferably 1 to 10 kgf. Further, the friability is 3.0% or less, preferably 2.5% or less, particularly preferably 2.0% or less.
The rapidly disintegrating solid preparation of the present invention obtained as described above is excellent in disintegration in the oral cavity or in water and has a hardness capable of withstanding distribution.

The disintegration time of the tablet obtained in the present invention in the oral cavity is desirably within 240 seconds, preferably within 210 seconds, and particularly preferably within 180 seconds. In addition, when tested according to the evaluation method of “(1) tablets” described in the 14th revised Japanese Pharmacopoeia, it disintegrates within 480 seconds, preferably within 420 seconds, and particularly preferably within 360 seconds. It is desirable and fully satisfactory.
The rapidly disintegrating solid preparation of the present invention is a tablet that is particularly easy to take for children and the elderly. Furthermore, since DFAIII is sweet, it can make a highly-preferred preparation and can be favorably taken even by generations such as children and the elderly who are resistant to tablets.
Examples of the present invention are shown below, but the present invention is not limited to these examples.

  2500 g of DFA III, 1000 g of sorbitol, 1000 g of corn starch and 485 g of crystalline cellulose were put into a V-type mixer (MIX WELL BLENDER V-20, manufactured by Deoksugaku Kosakusho) and mixed for 5 minutes. Further, 15 g of sucrose ester was added and mixed for 5 minutes. Next, using a rotary tableting machine (AP-22, manufactured by Hata Seiko Co., Ltd.), 750 mg tablets were obtained with two types of tableting pressures.

  DFAIII 2500g, trehalose 1250g, partially pregelatinized starch 750g and crystalline cellulose 485g are put into a fluidized bed granulator (FLO-5M, manufactured by Freund Sangyo) and water is added to 10 parts by mass with respect to 100 parts by mass of the mixed powder. After spraying, drying was performed at 80 ° C. so that the loss on drying was 2% or less. The granules obtained by drying and 15 g of sucrose ester were put into a V-type mixer (MIX WELL BLENDER V-20, manufactured by Deoksugakusho) and mixed for 5 minutes. Next, using a rotary tableting machine (AP-22, manufactured by Hata Seiko Co., Ltd.), 750 mg tablets were obtained with two types of tableting pressures.

  DFA III 1500 g, scallop shell calcium 900 g, xylitol 1000 g, trehalose 600 g, partially pregelatinized starch 400 g, corn starch 200 g, and crystalline cellulose 385 g are charged into a fluidized bed granulator (FLO-5M, manufactured by Freund Sangyo) and water is added while flowing. After spraying to 10 parts by mass with respect to 100 parts by mass of the mixed powder, drying was performed at 80 ° C. so that the loss on drying was 2% or less. The granules obtained by drying and 15 g of sucrose ester were put into a V-type mixer (MIX WELL BLENDER V-20, manufactured by Deoksugakusho) and mixed for 5 minutes. Next, using a rotary tableting machine (AP-22, manufactured by Hata Seiko Co., Ltd.), 750 mg tablets were obtained with two types of tableting pressures.

[Comparative Example 1]
A tablet was obtained in the same manner as in Example 1 except that sucrose (commercially available) was used instead of DFAIII.

[Comparative Example 2]
Tablets were obtained in the same manner as in Example 2 except that reduced maltose (commercially available) was used instead of DFAIII.

[Comparative Example 3]
Tablets were produced in the same manner as in Example 3 except that lactose was used instead of DFAIII.

Test method 1. Hardness test Using a digital hardness tester (NEW SPEED CHECKER TS-75N, Okada Seiko), the hardness of 10 tablets was measured and the average value was displayed.
Test method 2. Intraoral disintegration time measurement In the oral cavity of a total of 5 healthy adult men and women (25 to 40 years old), the time until the tablet completely disintegrated with only saliva without water was measured, and the average value was shown. .

As shown in Table 1, in Examples 1, 2, and 3, the oral disintegration time was fast although all had sufficient hardness. The speed is as short as 1/3 to 1/4 of the corresponding comparative example. Further, no problem occurred when tableting.
On the other hand, in the reference example, the oral disintegration time was slow even with the same tablet hardness as in the comparative example. Furthermore, the tableting powder of the comparative example was poor in moldability and also showed sticking.
That is, in the oral disintegration time, moldability, and tabletability, the results of Examples were better than those of Comparative Examples.

Claims (3)

Excipients include sugar alcohols, starches and crystalline celluloses,
Free of sucrose, reduced maltose and lactose,
3 to 70% by mass of difructose anhydride III (hereinafter referred to as “DFA III”) , which is a rapidly disintegrating component of a solid preparation that disintegrates and exhibits functionality ,
A rapidly disintegrating tablet that disintegrates or dissolves within 180 seconds in the oral cavity. Minerals, vitamins, rapidly disintegrating tablet preparation according to claim 1, characterized in that it comprises one or more kinds selected from plant extracts,. Rapidly disintegrating tablet agent according to claim 1 or 2, wherein the particle size of the DFA III is 500μm or less.