JPH11116465A - Rapid dissolving preparation and method for producing the same - Google Patents

Abstract

(57) [Summary] [Problem] To provide a rapidly dissolving preparation which rapidly disintegrates and dissolves in a place where water is limited, such as in the oral cavity, and has a hardness sufficient for practical use. SOLUTION: A rapidly dissolving preparation obtained by dissolving and dispersing a drug, a saccharide and polyvinylpyrrolidone in an organic solvent and then removing the organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a rapid-dissolving preparation, and more particularly to a rapid-dissolving preparation which disintegrates and dissolves rapidly in a place where water is limited, such as in the oral cavity, and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, as a dosage form that is easy to take for patients, elderly people or children who have difficulty swallowing drugs,
The development of solid preparations that rapidly disintegrate and dissolve in the oral cavity is underway. For example, Japanese Patent Application Laid-Open Nos.
8-113124, JP-A-3-56412, JP-A-3-3-124
86837 and JP-A-9-502622 propose formulations using freeze-drying. In addition, Japanese Unexamined Patent Publication No.
8-194808 or JP-A-5-270154 proposes a production method using a wet tablet obtained by pressing a wet powder under low pressure and then drying.

Further, JP-A-58-194808, JP-A-6-502194, JP-A-5-310558, JP-A-8-99904, JP-A-8-208520, and JP-A-8-208520
208521, JP-A-8-333243, JP-A-9-7
In each of the publications of 1523, dissolution and melting in the oral cavity by compression molding are described.
Disintegrating solid formulations have been proposed and are described in WO 93/127.
No. 69 proposes a solid preparation obtained by dispersing a mixed powder of a drug and lactose and / or mannitol in an aqueous agar solution, filling the mixture into a mold, and then drying.

[0004] However, in each of the conventional preparations proposed above, it is difficult to formulate a drug which is unstable against moisture since water must be used during the manufacturing process. Removal requires a large amount of energy. In addition, in the preparation using the freeze-drying method, although the solubility in the oral cavity is very rapid because the preparation has a large porosity, the preparation itself is bulky and it is difficult to increase the drug content. Furthermore, the formulation is often difficult to store and handle on a daily basis because the formulation is fragile due to its low hardness and has high hygroscopicity. In addition, lyophilization has the disadvantage that the production process is complicated and the productivity of the preparation is low.

[0005] On the other hand, in a manufacturing method in which pressure molding is performed, the hardness can be increased not only by a normal compression molding but also by a manufacturing method using a wet tablet, but the dissolution / disintegration time in the oral cavity is increased. Often becomes longer. Furthermore, those using gelatin or agar, which are natural products, are liable to cause discoloration or the like with the passage of time, sometimes impairing the stability of the drug to be combined, and have the disadvantage that various bacteria are easily propagated.

[0006]

Accordingly, the present invention provides
Disintegrated quickly in the oral cavity, etc., solving the above-mentioned problems
It is an object of the present invention to provide a rapidly dissolving preparation which can be dissolved and has hardness sufficient for practical use, and a method for producing the same.

In order to solve such a problem, the present inventors have
We examined a method for manufacturing a solid preparation that rapidly disintegrates and dissolves in the oral cavity without performing pressure molding or freeze-drying.
After dissolving and dispersing the saccharide and polyvinylpyrrolidone in the organic solvent, the solid preparation obtained by removing the organic solvent by ventilation drying or drying under reduced pressure can be applied to a drug which is unstable to moisture. It can be manufactured without complicated manufacturing steps, and the obtained formulation has hardness that can withstand practical use, and disintegration and dissolution in the oral cavity are extremely rapid, and the drug is contained as necessary. The inventors have newly found that the amount can be increased and the stability is good, and completed the present invention.

[0008]

Means for Solving the Problems According to one aspect of the present invention, a drug, a saccharide and polyvinylpyrrolidone are dissolved and dispersed in an organic solvent, and then the rapidly dissolving preparation obtained by removing the organic solvent is obtained. I will provide a.

According to another aspect of the present invention, a drug, a saccharide, and polyvinylpyrrolidone are dissolved and dispersed in an organic solvent to obtain a suspension. A method for producing a rapidly dissolving preparation, comprising the steps of:

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The rapidly dissolving preparation provided by the present invention uses a combination of a saccharide and polyvinylpyrrolidone for a drug, forms a suspension dissolved and dispersed in an organic solvent, and then uses the organic solvent. It is characterized in that it is removed.

The kind of the drug used in the rapid dissolving preparation of the present invention is not particularly limited, and various kinds of drugs can be compounded. For example, the following can be exemplified as typical ones. Hypnotic sedatives, antiepileptics, antipyretic analgesics and anti-inflammatory drugs, stimulants, stimulants,
Drugs for central nervous system such as antianalgesics, drugs for psychiatric nerves; drugs for peripheral nerves such as skeletal muscle relaxants, autonomic drugs, autonomic nerve blockers, plant preparations, etc .; sensory organs such as ophthalmic drugs, otolaryngological drugs Drugs: Cardiovascular drugs, such as inotropic drugs, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasodilators, vasoconstrictors, vasodilators, and atherosclerotic drugs.

Further, drugs for respiratory organs such as respiratory stimulants and antitussive expectorants; drugs for gastrointestinal organs such as drugs for peptic ulcers, stomach digestive drugs, antacids, laxatives, bile drugs, and intestinal drugs; Hormonal drugs such as hormonal drugs and antihormonal drugs; urinary disinfectants, uterine constrictors,
Urogenital and anal drugs such as urogenital, hemorrhoidal and anal drugs; vitamins, nourishing tonics, drugs for blood and body fluids, drugs for liver diseases, antidote, addictive drugs, Metabolic drugs such as gout remedies, enzyme preparations, diabetes remedies, etc .; drugs for functioning tissue cells such as cell stimulants, tumor drugs, etc .; against pathogenic organisms such as antibiotics, chemotherapeutics, antiprotozoal drugs, anthelmintics, etc. Pharmaceuticals: Drugs such as alkaloid drugs and non-alkaloid drugs. These drugs may be used alone or in combination of two or more.

These drugs used in the present invention may be in the form of solid, powder or liquid as long as they can be dissolved or dispersed in a suspension as an organic solvent together with saccharide and polyvinylpyrrolidone. When the solid drug is finely pulverized and used as a fine powder, when it disintegrates and dissolves in the oral cavity, the feel is smooth and the feeling of taking is good. The drug used in the present invention may be encapsulated like a microcapsule, a microsphere, a nanocapsule, or a nanosphere. Further, two or more kinds of drugs can be arranged in different layers.

The amount of these drugs contained in the preparation provided by the present invention depends on the dose per dose and the physicochemical properties of the drug, but is preferably 60% by weight or less of the total solid components. , More preferably 40% by weight of the total solid components
It is as follows.

On the other hand, the saccharide used in the present invention is not particularly limited as long as it is soluble in water. As such saccharides, for example, monosaccharides, disaccharides, oligosaccharides, sugar alcohols, reducing sugars, isomerized sugars and the like can be used. More specifically, glucose, fructose, lactose, maltose,
Examples include sucrose, xylose, trehalose, dextrin, sorbitol, xylitol, mannitol, erythritol, maltitol, lactitol, lactulose, and the like. These saccharides can be used alone or as a mixture of two or more.

The amount of the saccharide used in the present invention together with the drug in the preparation varies depending on the properties of the drug used and the additives added together. In order to maintain the content, it is generally preferable to add 40% by weight or more, more preferably 60% by weight or more, as the total solid content of the preparation.

The amount of polyvinylpyrrolidone used together with the drug and the saccharide in the present invention varies depending on the properties of the drug and the additives to be added together. Generally, it is preferable to mix 1 to 20% by weight, more preferably 2 to 15% by weight, as the total solid content of the preparation.

In the rapidly dissolving preparation of the present invention, a drug,
As an organic solvent for dissolving and dispersing saccharides and polyvinylpyrrolidone, polyvinylpyrrolidone is well dissolved,
On the other hand, there is no particular limitation as long as the saccharide is hardly soluble, but a particularly preferred specific example is ethanol. Further, in the present invention, such an organic solvent can be used as a mixed solution with water, and when used as a mixed solution, water is preferably 30% by weight or less of the total solvent.

Thus, a preferred embodiment of the rapid dissolving preparation provided by the present invention is a drug having a total solid content of 60% by weight or less, preferably 40% by weight or less, and a drug having a total solid content of 40% by weight or more. Preferably, 60% by weight or more of saccharides and 1 to 20% by weight, preferably 2 to 15% by weight of total solids of polyvinylpyrrolidone are dissolved and dispersed in ethanol or an organic solvent which is a mixture of ethanol and water. It is a rapidly dissolving preparation obtained by drying afterwards.

The rapid-dissolving preparation of the present invention further comprises a natural or synthetic polymer compound, a sweetener, an acidulant, a flavor, a coloring agent as long as the disintegration / solubility and hardness are not significantly deteriorated. Etc. can be blended.

Specific examples of such natural or synthetic polymer compounds include starch such as potato starch, corn starch, rice starch, wheat starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl starch, and hydroxypropyl starch. And its derivatives; crystalline cellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted carboxymethylcellulose sodium, croscarmellose sodium, acetic acid Cellulose, cellulose acetate phthalate, hydroxy Methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose and its derivatives such as crystalline cellulose, carboxymethyl cellulose sodium.

Further, gum arabic powder, tragacanth gum, karaya gum, gum ghatti, pectin, arabinogalactan, quince, locust bean gum, guar gum, tamarind seed polysaccharide, alginic acid, carrageenan, furceleran, xanthan gum, curdlan, casein, albumin, etc. Natural polymer compound: polyvinyl acetate, macrogol, polyvinyl alcohol, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, carboxyvinyl polymer And synthetic high molecular compounds such as polyvinyl acetal diethylaminoacetate and dimethylpolysiloxane.

Specific examples of the sweetener include glycyrrhizin, disodium glycyrrhizinate, trisodium glycyrrhizinate, stevia, stevioside, rebaudioside, saccharin, saccharin sodium, aspartame and the like.

Further, specific examples of the acidulant include citric acid, tartaric acid, malic acid, etc. Specific examples of the flavor include strawberry, lemon, lemon lime, orange, peppermint, peppermint oil, menthol, and the like. Is mentioned. Specific examples of the coloring agent include caramel, anato extract pigment, β-carotene, beet red, and the like.

The size and shape of the rapidly dissolving preparation of the present invention as a preparation form are not particularly limited.
For example, granules, pellets, tablets, suppositories and the like can be used as ordinary preparations, and among them, tablets are preferable.

The method for producing the rapidly dissolving preparation of the present invention can be specifically carried out as follows. That is, an organic solvent is added to a mixed powder of a drug, a saccharide and polyvinylpyrrolidone, and the suspension is dissolved and dispersed to form a suspension. The suspension is filled in a hole of a desired preparation mold, for example, a concave mold, and dried. Thereby, the desired preparation can be obtained. Incidentally, polyvinylpyrrolidone may be dissolved in an organic solvent and added to the mixed powder of the drug and the saccharide. Drying can be performed by ventilation drying or drying under reduced pressure at room temperature.

[0027]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 15 g of quazepam, 169.5 g of sucrose, 50 g of corn starch, 2 g of aspartame and 0.5 g of l-menthol were uniformly mixed. Next, a liquid in which 12.5 g of polyvinylpyrrolidone was dissolved in 150 g of ethanol was added to the mixed powder and mixed to obtain a suspension. This suspension was filled into a concave hole having a diameter of 9 mm in an amount of 400 mg each,
And dried under reduced pressure for 12 hours to obtain a rapidly dissolving preparation of the present invention.

Example 2 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1 except that trehalose was used instead of sucrose.

Example 3 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1, except that mannitol was used instead of sucrose.

Example 4 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1 except that erythritol was used instead of sucrose.

Example 5 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1 except that sorbitol was used instead of sucrose.

Example 6 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1 except that lactose was used instead of sucrose.

Example 7 Instead of sucrose in Example 1, powdered reduced maltose syrup was used.
Otherwise, a rapid dissolving preparation of the present invention was obtained in the same manner.

Example 8 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1 except that xylitol was used instead of sucrose.

Example 9 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1 except that glucose was used instead of sucrose.

Example 10 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1 except that fructose was used instead of sucrose.

Example 11 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 1, except that dextrin was used instead of sucrose.

Test Example 1 The hardness of each of the preparations produced in Examples 1 to 11 was measured with a tablet hardness tester (TH-303RP type, manufactured by Toyama Sangyo). In addition, the disintegration time, using purified water as a test solution,
It was measured according to the Japanese Pharmacopoeia 13 revised disintegration test method. In addition, the oral dissolution time was measured. The results are summarized in Table 1.

[0040]

[Table 1]

As is evident from the results in the table, the formulation of the present invention has a hardness that can withstand practical use, and a dissolution time in the oral cavity of about 30 seconds or less. Is understood.

Example 12 15 g of quazepam, 177 g of sucrose, 5 corn starch
0 g, 2 g of aspartame, 0.5 g of 1-menthol and 5 g of polyvinylpyrrolidone were uniformly mixed. Next, 150 g of ethanol was added to the mixed powder and mixed,
A suspension was obtained. This suspension is placed in a concave hole having a diameter of 9 mm.
After filling each in an amount of 00 mg and drying by ventilation at 30 ° C. for 3 hours,
After drying under reduced pressure for 12 hours, a rapidly dissolving preparation of the present invention was obtained.

Example 13 The procedure of Example 12 was repeated, except that the amount of sucrose was changed to 157 g and the amount of polyvinylpyrrolidone was changed to 25 g.
A rapidly dissolving formulation of the invention was obtained.

Example 14 A rapidly dissolving preparation of the present invention was obtained in the same manner as in Example 12, except that the amount of sucrose was changed to 144.5 g and the amount of polyvinylpyrrolidone was changed to 37.5 g.

Comparative Example 1 The procedure of Example 12 was repeated, except that the amount of sucrose was changed to 127 g and the amount of polyvinylpyrrolidone was changed to 55 g.
The preparation of Comparative Example 1 was obtained.

Comparative Example 2 A preparation of Comparative Example 2 was obtained in the same manner as in Example 12 except that the amount of sucrose was changed to 182 g and polyvinylpyrrolidone was used.

Test Example 2 The hardness and disintegration time of the preparations of the present invention prepared in Examples 12 to 14 and the preparations of Comparative Examples 1 and 2 were measured in the same manner as in Test Example 1. Table 2 summarizes the results.

[0048]

[Table 2]

As is clear from the results in the table, the preparation of Comparative Example 2 to which no polyvinylpyrrolidone was added was very brittle. In the preparation of Comparative Example 1 in which the amount of polyvinylpyrrolidone was large, the disintegration time was as long as 4 minutes or more. On the other hand, it is understood that the formulation of the present invention has a hardness that can be put to practical use, has a fast disintegration time, and is particularly excellent.

Example 15 15 g of quazepam, 179.5 g of sucrose, 50 g of corn starch, 2 g of aspartame, 0.5 l-menthol
g and 2.5 g of polyvinylpyrrolidone were uniformly mixed. Then add 105 g of ethanol and 45 g of water
Was added and mixed to obtain a suspension. This suspension was filled into a concave hole having a diameter of 9 mm in an amount of 400 mg, and the suspension was heated at 30 ° C.
And dried under reduced pressure for 12 hours to obtain a rapidly dissolving preparation of the present invention. The hardness of this formulation is 1.58K
g (average value of 10 samples), disintegration time was 8.3 seconds (average value of 6 samples), and dissolution time in the oral cavity was 37.3 seconds (average value of 3 users).

Example 16 Pyridoxine hydrochloride 30 g, erythritol 151 g, corn starch 50 g, citric acid 1 g, aspartame 1
g and 2 g of perfume were uniformly mixed. Next, a solution prepared by dissolving 15 g of polyvinylpyrrolidone in 110 g of ethanol was added to the mixed powder and mixed to obtain a suspension. This suspension was filled into a concave hole having a diameter of 10 mm by 360 mg,
After air drying at 30 ° C. for 3 hours, drying under reduced pressure for 12 hours,
A rapidly dissolving formulation of the invention was obtained. The dissolution time in the oral cavity of this preparation was 19.7 seconds (average value of three persons).

Example 17 30 g of pyridoxine hydrochloride, 151 g of xylitol, 50 g of corn starch, 1 g of citric acid, 1 g of aspartame
And 2 g of perfume were uniformly mixed. Next, a solution in which 15 g of polyvinylpyrrolidone was dissolved in 100 g of ethanol was added to the mixed powder and mixed to obtain a suspension. This suspension was filled into a concave hole having a diameter of 10 mm by 350 mg, and 3
After drying with air at 0 ° C. for 3 hours, the mixture was dried under reduced pressure for 15 hours to obtain a rapidly dissolving preparation of the present invention. The dissolution time in the oral cavity of this formulation was 16 seconds (average of three persons).

[0053]

The rapid-dissolving preparation of the present invention provided as described above disintegrates and dissolves rapidly in the oral cavity, so that it is easy to take and has a hardness that can withstand practical use. Therefore, ordinary handling is easy. further,
Since the production method does not require freeze-drying, it can be produced efficiently. Further, since it can be produced without using water, it has an advantage that it can be applied to drugs which are unstable in water.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor, Keiichi Kasai 2-2-11-102, Azuma, Narita-shi, Chiba Prefecture

Claims (10)

[Claims] 1. A rapidly dissolving preparation obtained by dissolving and dispersing a drug, a saccharide and polyvinylpyrrolidone in an organic solvent and then removing the organic solvent. 2. The method according to claim 1, wherein the drug is 60% by weight or less of the total solids, the saccharide is 40% by weight or more of the total solids, and the polyvinylpyrrolidone is 1 to 20% by weight of the total solids. Fast dissolving formulation. 3. The method according to claim 1, wherein the drug is 40% by weight or less of the total solids, the saccharide is 60% by weight or more of the total solids, and the polyvinylpyrrolidone is 2 to 15% by weight of the total solids. Fast dissolving formulation. 4. The rapidly dissolving preparation according to claim 1, wherein the organic solvent is ethanol. 5. The rapidly dissolving preparation according to claim 1, wherein the organic solvent is a mixture of ethanol and water. 6. The rapidly dissolving preparation according to claim 1, further comprising a natural or synthetic polymer. 7. The rapid dissolving preparation according to claim 1, further comprising at least one of a sweetener, an acidulant, a flavor, and a coloring agent. 8. A rapid dissolving method comprising dissolving and dispersing a drug, a saccharide and polyvinylpyrrolidone in an organic solvent to obtain a suspension, filling the suspension into a preparation mold, and removing the organic solvent. For the production of sexually active preparations. 9. The method according to claim 8, wherein the drug is 60% by weight or less of the total solids, the saccharide is 40% by weight or more of the total solids, and the polyvinylpyrrolidone is 1 to 20% by weight of the total solids. Manufacturing method of rapidly dissolving preparation. 10. The method according to claim 8, wherein the drug is 40% by weight or less of the total solids, the saccharide is 60% by weight or more of the total solids, and the polyvinylpyrrolidone is 2 to 15% by weight of the total solids. Manufacturing method of rapidly dissolving preparation.