JP3418274B2 - Tablets with good oral feel - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tablet which is used in the fields of luxury goods or medicine and which is rapidly disintegrated in the oral cavity and has smoothness without leaving roughness.

[0002]

2. Description of the Related Art Preparations applied to the oral cavity have been devised in various ways depending on the purpose such as fast disintegration, smooth mouth feel, taste and the like.

JP-A-52-76420, JP-B-5
8-24410, JP-A 61-15830, JP-A-1-501704, JP-A-5-271.
054 describes a porous tablet that disintegrates rapidly in the mouth. These are formed by freeze-drying or natural drying after adding a solvent such as water to a mixture containing a medicinal ingredient and a sugar, and after compression-molding a mixture containing a medicinal ingredient, a sugar and water. It was dried to give a porous tablet.

In Japanese Patent Laid-Open No. 6-293634, the wear resistance of plain tablets is enhanced by adding a small amount of a low melting point oily substance to tablets. Here, the low melting point oily substance is added for the purpose of improving the abrasion resistance of the uncoated tablet.

It is well known that fats and oils make the mouthfeel of foods smooth. In JP-A-58-194808, by adding fats and oils and a surfactant to a tablet, an emulsion having a smooth creamy pleasant flavor is quickly disintegrated in the mouth, and the emulsion has no "roughness". Chewable tablets are described.

Sugihara et al. (Pharmacia, 1396, 30,
1994) is Macrogol 100 that dissolves in the oral cavity.
0. By using fats and oils that melt at the temperature in the oral cavity as a base, an oral soluble preparation that is easy for the elderly to take is obtained. In this formulation, the heat-melted products are filled in a PVC pocket used for PTP and then allowed to cool.

The oral cavity is a region which is very sensitive to the feeling and flavor such as irritation and foreign body sensation. When the lesion such as a wound or inflammation is in the oral cavity, the feeling becomes more sensitive. Therefore, it is very important that the preparation applied to the oral cavity has a mouth feel such as irritation, roughness and smoothness, and a flavor such as sweetness and bitterness. Especially in tablets, disintegration and solubility greatly affect the feel in the oral cavity.

[0008] However, those which satisfy all of the requirements such as rapid disintegration, smooth texture without leaving roughness, no breakage during production and storage, and easy molding by compression, are the above-mentioned conventional preparations. Is absent in.

[0009]

DISCLOSURE OF THE INVENTION Accordingly, discomfort and discomfort are caused even when the oral cavity has a defect such as a wound or inflammation due to its rapid disintegration in the oral cavity and smoothness without leaving roughness. A tablet to be applied in the oral cavity that does not give is desired.

Usually, in order to improve the disintegration property, a polymer is added as a disintegrant. When an insoluble polymer is used, good disintegration is imparted, but the discomfort in the oral cavity is often given as described above. Therefore, it is desired that the insoluble polymer is not added.

Further, since tablets that rapidly disintegrate have low strength, tablets that can be manufactured by a simple operation and that are not broken during manufacture and storage are desired.

[0012]

As a result of various studies, the present inventors have used oils and fats / excipients to produce a first granule containing the fats and oils and the excipient and a second granule containing the excipient. Each manufactured,
The present invention has been completed by finding that a tablet which is compression-molded with other additives, if necessary, solves the above-mentioned problems. That is, the present invention firstly comprises a composition containing both (a) oils and fats and first granules containing an excipient as an essential component, and (b) second granules containing no oils and fats as an essential component. It is a fat-and-oil-containing tablet obtained by compression-molding a product.

Second, the excipient is a water-soluble saccharide, and the composition containing both the first granule and the second granule contains a medicinal component and does not contain a water-insoluble polymer. It is a tablet.

Thirdly, an oil-containing tablet which is a solid oil having a melting point or a melting point of 30 to 37 ° C. when mixed with an excipient or the like.

Fourthly, the content of fats and oils is 7 to 30% by weight based on the whole first granules, the excipient content is 70 to 93% by weight based on the whole first granules, and the whole tablet. Is a fat-and-oil-containing tablet containing 3 to 20% by weight of fats and oils and 85 to 97% by weight of the total amount of excipients including those of the second granules.

Fifth, the first and second granules have the following composition: Oil-and-fat-containing preparation according to claim 1, first granules and fats 3 to 15% Excipients 15 to 40% Buprenorphine hydrochloride 0.05 to 1 % Second granule Water-soluble saccharide 40-80% Other ingredients 0.1-2%

The present invention will be described in detail below. As the oils and fats used in the present invention, oils and fats usually used for medicines and foods can be used, but from the viewpoint of improving disintegration in the oral cavity, at room temperature (15 to 30 ° C). It is a solid and has a melting point of 30 to 37 ° C. (about body temperature) or lower, or a melting point alone that is higher than body temperature, or a melting point when mixed with sugar and / or a medicinal component is lower than body temperature. Good. For example, vegetable fats and oils and hydrogenated oils thereof, animal fats and oils and hydrogenated oils thereof, and synthetic glycerides are used.

The vegetable oils and fats include corn oil, soybean oil, safflower oil, coconut oil, palm oil, castor oil,
Cocoa butter is used. As the animal fat and oil, milk fat, lard, beef tallow, herring oil and the like are used. As the synthetic glyceride, medium chain fatty acid triglyceride, hard fat and the like are used.

Preferred fats and oils are hard fat, medium chain fatty acid triglyceride, cocoa butter and palm oil. They may be commercially available products, for example, Witepsol (registered trademark, Mitsuba Trading Co., Ltd.) as a hard fat.

The content of fats and oils is not particularly limited as long as it can be granulated, but is usually 2% by weight or more, preferably 5% by weight based on the whole granules containing fats and oils, that is, the first granules.
Wt% or more, more preferably 7 wt% or more, and 90
It is not more than 60% by weight, preferably not more than 30% by weight, more preferably not more than 30% by weight. Further, it is usually 1% by weight or more, preferably 3% by weight or more, based on the whole tablet,
In the case of tablets that are more easily disintegrated, 4% by weight or more is preferable. The upper limit varies depending on the intended tablet and cannot be generally determined, but is 80% by weight or less, preferably 40% by weight or less, and more preferably 20% by weight or less.

The excipients used in the present invention may be those used in ordinary pharmaceutical excipients, but water-soluble excipients are preferable in consideration of oral preparations such as sublingual tablets. Sugars are preferred as the water-soluble excipient. As the saccharide, starch, any saccharide other than water-insoluble polysaccharides such as cellulose, that is, any water-soluble saccharide, for example,
Monosaccharides, oligosaccharides, sugar alcohols and the like are used, and the saccharides may be used alone or in combination of two or more kinds.

As the monosaccharide, glucose, fructose, etc. are used. As oligosaccharides, lactose, maltose, sucrose,
Dextrin or the like is used. As the sugar alcohol, sorbitol, xylitol, mannitol and the like are used.

Preferred as the above-mentioned saccharides are, for example, lactose, sucrose, sorbitol, mannitol and the like, alone or in combination of two or more kinds. The excipients of the first granules and the second granules may be different, but it is preferable that they are the same.

The content of the excipient is usually 10% by weight or more, preferably 40% by weight or more, more preferably 70% by weight based on the whole first granules in the granules containing oils and fats (hereinafter referred to as the first granules). It is not less than 98% by weight, preferably not more than 95% by weight, more preferably not more than 93% by weight.

Further, in the granules containing no fats and oils (hereinafter referred to as the second granules), 100% by weight of the entire second granules may be composed of an excipient, and may contain other additives such as a binder. In that case, the content of the excipient is 95% by weight or more, more preferably 97% by weight, based on the whole second granules.
In the above, the balance is other additives. The content of excipients in the tablet (total amount of excipients in the first granule and the second granule) is usually 20% by weight or more, preferably 60% by weight or more, more preferably 85% by weight, based on the whole tablet. % And 99% by weight or less, preferably 97% by weight or less, and 96% by weight or less in the case of tablets that are more easily disintegrated.

To produce the first granules, when the oils and fats are liquid, they are uniformly mixed with an excipient by a method such as kneading,
It can be obtained by granulation by a conventional method such as extrusion granulation. When a solid product is used, it can be obtained by mixing the pulverized product as it is, or by heat-melting and uniformly mixing by a method such as kneading, and then granulating by a conventional method.

At the time of this granulation, fats and oils are adsorbed and supported by an excipient and also serve as a binder in the granules.

The second granules can be produced by adding water or alcohol, or the binder as it is, or dissolving the binder in a solvent, and adding it to the above-mentioned excipients, and granulating by a conventional method. it can.

Examples of the binder include water-soluble polymers such as saccharides (the same saccharides as the above-mentioned excipients) and hydroxypropyl cellulose. From the viewpoint of disintegration, saccharides such as oligosaccharides and sugar alcohols are preferable, sucrose and lactose among oligosaccharides, and sorbitol among sugar alcohols.

The tablet of the present invention is not necessarily required to contain a medicinal component, but it is usually used as a medicinal preparation by incorporating the medicinal component. The medicinal component used in the present invention may be in the form of liquid or powder, and may be any medicinal component, and a medicinal component that can be orally administered is used. When the tablet of the present invention is an intraoral preparation such as a sublingual tablet, a medicinal component that is absorbed from the oral mucosa is more preferable. Examples include angina pectoris, analgesics, and vitamins.

Examples of the angina drug include nitroglycerin, isosorbide dinitrate and the like. Examples of the analgesics include antipyretic and analgesic anti-inflammatory agents such as aspirin, acetaminophen and ibuprofen, and central analgesics such as morphine sulfate, codeine phosphate and buprenorphine hydrochloride. Examples of vitamins include vitamins A, vitamins B and vitamins C.

The medicinal ingredient may be blended in the first granule or the second granule, or the medicinal ingredient may be mixed with the first granule and the second granule before compression molding to give a tableting composition. For example, in the case of buprenorphine hydrochloride, it is usually preferable to mix it in the first granule, although it depends on the kind of the medicinal component. When blended in the first granule, the amount of the excipient may be reduced by the amount corresponding to the blended medicinal component. In addition, when the content of the medicinal component is high and cannot be blended only in the first granule, the medicinal component may be contained in the second granule, and the medicinal component is separately contained together with the first granule and the second granule. In addition to the above, a tableting composition may be prepared by thoroughly mixing.

The content of the medicinal component varies depending on the kind of medicinal component, etc., but is usually 0.001 to 4 with respect to the whole tablet.
It is 0% by weight, preferably 0.01 to 20% by weight, and more preferably 0.01 to 10% by weight.

Examples of other additives which are added as necessary include lubricants, flavoring / flavoring agents, colorants and the like.

Examples of the lubricant include magnesium stearate, stearic acid, talc and the like. Examples of the corrigent include artificial sweeteners such as sodium saccharin and aspartame, acidulants such as citric acid, malic acid and tartaric acid, and flavors such as menthol, lemon and orange. Examples of the colorant include those used for food such as Food Yellow No. 5.

These additives are one kind or two or more kinds,
It can be added to the extent that the characteristics of the present invention are not impaired. These additives may be added to the first granules or the first and second granules, or may be used separately and separately in the granules and compounding prior to compression molding.

The tablets of the present invention are prepared by blending the first granules, the second granules, and other additives as required, mixing them well, and then compression-molding them by a conventional method such as tablet molding. You can

The mixing ratio of the first granules and the second granules is such that the amount of the granules containing fats and oils is 2 to 90% by weight, preferably 20.
The ratio is about 60% by weight, and this ratio depends on the amount of fats and oils in the granules. The preferred composition ratios when the tablet of the present invention contains a medicinal component is as follows. The composition ratio (%) indicates the ratio (% by weight) to the whole tablet.

[0039] First granule Oils and fats 2-20% Excipient 8-60% Medicinal ingredient 0.01-20% Second granule Excipient 30-85% Binder 0.1-5% Other additives 0-5%

The preferred composition ratios when the medicinal component is an analgesic such as buprenorphine hydrochloride are shown below. The composition ratio (%) indicates the ratio (% by weight) to the whole tablet. 1st granular oils and fats 3 to 15% Excipients 15 to 40% Pharmaceutically active ingredient 0.05 to 1% Second granular water-soluble sugars 40 to 80% Other ingredients 0.1 to 2%

[0041]

The action and effect of the present invention will be specifically shown by test examples. Test Example 1 Measurement of hardness, disintegration time, friability

1. Sample of the present invention: The tableting punches of Examples 1 to 6 were 5.5 mmφ flat type. However, in the friability test, the flat tablet was apt to be chipped at the edges and was not suitable. Further, in (1) hardness measurement and (2) disintegration time, some tablets obtained by changing the tableting pressure were measured and expressed as the maximum measured value. Also, (3) the quantity used in the friability test is 3
It was 0 tablets.

2. Test method (1) Hardness measurement It was measured using a speed checker (Okada Seiko). (2) Disintegration time A disintegration tester (model T-2S Toyama Sangyo) was used and distilled water was used as the test solution, and the disintegration test was performed according to the disintegration test method described in the 12th revision of the Japanese Pharmacopoeia. (3) Friability test Using a friability tester (Kayagaki Seisakusho), 30 at 25 rpm
Measure for minutes, divide the weight loss after measurement by the weight before measurement,
It was multiplied by 100 and expressed as a percentage.

3. Test results It is as shown in Table 1.

[0045]

[Table 1]

When a composition having a composition similar to that of the tablet of the present invention is uniformly mixed into the first granules and the second granules and tableted in the same manner as in the present invention, the hardness is 1 tablet. Witepsol content of 10% by weight 1.7k
It is about 2.2 kg at 5% by weight, and the disintegration time is 10
Since the weight% is 18 seconds, the 5% by weight is about 25 seconds, and the friability is 10% by weight is about 4.30%, the tablet obtained according to the present invention has good disintegration and improved strength. I understand.

[0047]

The present invention will be described in more detail with reference to the following examples, which are not intended to limit the present invention.

Example 1 2.0 g of Witepsol H-5 (registered trademark, Mitsuba Trading Co., Ltd.) was weighed in a mortar and heated and melted. Lactose 8.0g
In addition to the weighed in a mortar, well kneaded, while the Witepsol H-5 not solidify, granulated extruded at 250μm sieve, after cooling to room temperature, sieved with sieve 297Myuemu, oils and fats It was the first granule contained. 2 ml of 0.4 g of sorbitol dissolved in 4 ml of water was added to 19.8 g of lactose weighed in a mortar and kneaded well.
Extrude and granulate with a 250μm sieve, 40 ℃, 120
After drying for a minute and under reduced pressure, the particles were sized with a 297 μm sieve to obtain second granules containing no fat. After thoroughly mixing 5.0 g of the first granule and 4.95 g of the second granule, 0.05 g of magnesium stearate was added and mixed, and the mixture was compression molded using a single tableting machine (KT-2 type, Okada Seiko) to give tablets. And The composition of Example 1 is shown in Table 2.

[0049]

[Table 2]

Example 2 The first granules containing oil and fat were prepared in the same manner as in Example 1. 2m of 0.4g of white sugar dissolved in 4ml of water
1 was added to 19.8 g of lactose weighed in a mortar and kneaded well. Extrude and granulate with a 250 μm sieve, 40
After drying under reduced pressure at 120 ° C. for 120 minutes, the particles were sized with a 297 μm sieve to obtain second granules containing no fat or oil. First granule 5.0
g and 4.95 g of the second granules were mixed well, 0.05 g of magnesium stearate was added and mixed, and tablets were prepared in the same manner as in Example 1. The composition of Example 2 is shown in Table 3.

[0051]

[Table 3]

Example 3 1.0 g of Witepsol H-5 (registered trademark, Mitsuba Trading Co., Ltd.) was weighed in a mortar and heated and melted. Lactose 9.0g
Was weighed out and added to a mortar, kneaded well, and extruded through a 250 μm sieve to granulate before Witepsol H-5 was solidified, cooled to room temperature, and then sized with a 297 μm sieve to remove fats and oils. It was the first granule contained. The second granules were prepared in the same manner as in Example 1 and contained no fat or oil. After thoroughly mixing 5.0 g of the first granules and 4.95 g of the second granules, 0.05 g of magnesium stearate was added and mixed, and tablets were prepared in the same manner as in Example 1. The composition of Example 3 is shown in Table 4.

[0053]

[Table 4]

Example 4 1.0 g of Witepsol H-5 (registered trademark, Mitsuba Trading Co., Ltd.) was weighed in a mortar and heated and melted. Lactose 9.0g
Was weighed out and added to a mortar, kneaded well, and extruded through a 250 μm sieve to granulate before Witepsol H-5 was solidified, cooled to room temperature, and then sized with a 297 μm sieve to remove fats and oils. It was the first granule contained. 2 ml of 0.4 g of sucrose dissolved in 4 ml of water was added to 19.8 g of lactose weighed in a mortar and kneaded well.
Extrude and granulate with a 250μm sieve, 40 ℃, 120
Minutes, dried under reduced pressure with an aspirator, and sized with a 297 μm sieve to obtain second granules containing no fat. After thoroughly mixing 5.0 g of the first granules and 4.95 g of the second granules, 0.05 g of magnesium stearate was added and mixed, and tablets were prepared in the same manner as in Example 1. The composition of Example 4 is shown in Table 5.

[0055]

[Table 5]

Example 5 A first granule containing oil and fat was prepared in the same manner as in Example 1. The second granules were prepared in the same manner as in Example 1 and contained no fat or oil. After thoroughly mixing 7.45 g of the granules with 2.5 g of the granules, 0.05 g of magnesium stearate was added and mixed, and tablets were obtained in the same manner as in Example 1. The composition of Example 5 is shown in Table 6.

[0057]

[Table 6]

Example 6 7.94 g of lactose was weighed in a mortar, and 0.04 g of buprenorphine hydrochloride was added and mixed well. Witepsol H-5 (registered trademark, Mitsuba Trading) 2.0 in another mortar
After weighing g and heating and melting, a mixture of buprenorphine hydrochloride and lactose was added and kneaded well, and Witepsol H-5 was added.
While not solidifying, the mixture was extruded and granulated through a 250 μm sieve, cooled to room temperature, and then sized through a 297 μm sieve to obtain a first granule containing oil and fat. Sorbitol 0.4g
2 ml of 4 ml of water dissolved in 4 ml of water was added to 19.8 g of lactose weighed in a mortar and kneaded well. The mixture was extruded and granulated with a 250 μm sieve, dried under reduced pressure with an aspirator at 40 ° C. for 120 minutes, and then sized with a 297 μm sieve to obtain oil-free second granules. First granule 5.0g and second
After thoroughly mixing 4.95 g of the granules, 0.05 g of magnesium stearate was added and mixed, and tablets were obtained in the same manner as in Example 1. The composition of Example 6 is shown in Table 7.

[0059]

[Table 7]

[0060]

The formulation of the present invention rapidly disintegrates in the oral cavity and contains no water-insoluble polymer, so that all of the main ingredients in the formulation are dissolved or melted, so that no roughness is left and oils and fats are not contained. It is a tablet that gives a smooth feel in the oral cavity by containing it. Further, the present invention provides a tablet having improved strength by mixing two granules, that is, by mixing soft granules containing fats and oils with hard granules containing no fats and oils and tableting.

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Claims (4)

(57) [Claims] 1. (a) Room temperature solid, having a melting point of 30 ° C. to 37 ° C.
The first granules containing the fats and oils and the excipient which are
(B) An orally disintegrating oil-and-fat-containing tablet obtained by compression-molding a composition containing both second granules containing no fats and oils and an excipient as an essential component. 2. An excipient is a water-soluble saccharide, and a composition containing both the first granule and the second granule is a composition containing a medicinal component and not a water-insoluble polymer. The orally disintegrating oil-and-fat-containing tablet described. 3. The content of oils and fats is 7 to the entire first granules.
At 30% by weight, the excipient content is 70 based on the entire first granule.
~ 93% by weight, and 3 parts by weight of oils and fats
The orally disintegrating oil-and-fat-containing tablet according to claim 1 or 2, wherein the amount of the excipient is 60 to 97% by weight in total including the second granules. 4. The orally disintegrating fat-and-oil-containing tablet first granules and fats according to claim 1, wherein the first granules and the second granules have the following composition with respect to the whole tablet: 3 to 15% Excipient: 15 to 40% Hydrochloric acid Buprenorphine 0.05-1% Second granule water-soluble sugar 40-80% Other ingredients 0.1-2%