JPH07187993A - Base for preparation - Google Patents

Abstract

PURPOSE:To obtain a base for preparation, excellent in reproducibility of sustained release property, easy to control it and excellent in flexibility, elasticity and stretchability. CONSTITUTION:This base for preparation is obtained by dissolving hydroxypropyl cellulose and/or polyvinyl pyrrolidone and a tannin in a solvent capable of dissolving them and subsequently removing the solvent. The base obtained by this invention is excellent in release properties of the main drug and its control and can be suitably used as a substrate for a plaster agent for the mucous membrane in the oralcaurity after admixing a plasticizer therewith or without applying any treatment. It can also be used, e.g. as a base for a suppository, a substitute for adhesive plaster gauze and a skin-contacting surface member of a plaster for suppurative diseases.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel pharmaceutical base. More specifically, the present invention relates to a preparation base suitably used for sustained-release preparations for oral cavity, sustained-release preparations for rectal mucous membranes, sustained-release preparations for vaginal mucosa, wound protectants, patches for potential diseases, sustained-release tablets and the like.

[0002]

2. Description of the Related Art Oral sustained-release preparations include oral mucosal patches with or without a support layer, buccal tablets, sublingual tablets, troches, chewable tablets, etc. However, there were problems such as being complicated and having insufficient releasability or poor reproducibility, or being difficult to control the sustained release. And for the oral mucosa patch using a support layer, the support layer often has to be one that impedes drug permeation, and for that purpose, an enteric material such as ethyl cellulose is used, so that the flexibility is insufficient. There is a problem that a foreign substance is apt to occur, and that when it is attached to a convex portion, it easily peels off. Suppositories and ointments are known as rectal mucosa sustained-release preparations, but they have problems such as discomfort and stains on clothes. Suppositories and patches are known as vaginal mucosal sustained-release preparations, but they have problems such as discomfort and easy peeling. As wound-protecting agents, there are bandages and (bandages), which may cause irritation or softness. There was a problem of insufficient sex. The patch for concentrated diseases had problems with irritation and flexibility.

[0003]

SUMMARY OF THE INVENTION Therefore, the object of the present invention is to provide a sustained-release reproducible and easy-to-control, flexible, elastic, and stretchable base for preparations. Is to provide. Furthermore, it does not feel uncomfortable when used as a material for the gauze part of a plaster or the skin contact part of a patch for purulent diseases, and when used as a suppository or ointment, it does not stain clothes and is irritating. It is to provide a base material for a pharmaceutical product having a low content.

[0004]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in view of the above objects, hydroxypropyl cellulose (hereinafter sometimes referred to as “HPC”) and / or polyvinylpyrrolidone (hereinafter referred to as “PVP”) (Sometimes noted below) and a tannin substance are dissolved in a solvent in which these substances are soluble, and the composition obtained by removing the solvent is
The inventors have completed the present invention, knowing that it has excellent properties as a base for various sustained-release preparations. The present invention provides (1) a formulation base obtained by dissolving hydroxypropylcellulose and / or polyvinylpyrrolidone and a tannin substance in a solvent in which these substances are soluble, and (2) the tannin substance is tannic acid. And / or gallic acid as a base for the preparation according to the above (1), (3) a base for preparation according to the above (1) using a combination of hydroxypropyl cellulose and tannic acid,
(4) Hydroxypropylcellulose and polyvinylpyrrolidone and tannic acid in combination are used for the formulation base according to (1) above, (5) The ratio of hydroxypropylcellulose and / or polyvinylpyrrolidone to the tannin substance is 1000 by weight. (1) The above-mentioned (1), which comprises 1 to 5: 1 of the pharmaceutical base according to (1) above, and (6) a plasticizer.
The present invention relates to the pharmaceutical base according to the above (1), and the pharmaceutical base according to the above (1), which is provided with an adhesive layer.

The HPC used in the present invention may have a commonly used molecular weight in the range of 10,000 to 1,000,000, but the molecular weight of 20,000 to 1,
Those of, 000,000 are preferably used. Particularly, those having a molecular weight of 100,000 to 1,000,000 are preferably used, and the molecular weight of 20,000 to 100,000.
No. 0 may be added to control the solubility of the base material of the present invention. The PVP used in the present invention may have a commonly used molecular weight in the range of 5,000 to 2,000,000, but 30,000 to 2,0.
It is preferable to use one having a range of 0,000. The tannin substance used in the present invention includes tannic acid,
Examples include gallic acid. The solvent used in the present invention is not particularly limited as long as each material can be dissolved,
Further, a material that can uniformly disperse each material is also used, but ethanol or a mixed solvent of ethanol and water,
Methylene chloride or the like is preferably used. The pharmaceutical base obtained in the present invention can be suitably used as it is or as a support layer of an oral mucosal patch by blending a plasticizer.
It can also be used as a base for suppositories, a substitute for gauze for adhesive plasters, a skin contact surface member for patches for purulent diseases, and the like. Furthermore, during preparation, it is possible to add various drugs and plasticizers at the time of preparation, and various very good sustained release preparations (eg lozenges, buccal, oral mucosal patches, etc. Tablets etc.) can be obtained. In addition, an oral mucosa patch can be prepared by laminating a drug-containing adhesive layer on a support layer, which is a base for preparations obtained by the present invention, by a conventional method. Agents can also be laminated. In the base of the present invention, as the plasticizer to be optionally used, those usually used in this field are used, but propylene glycol, butylene glycol, macrogol, sorbitol, polyhydric alcohols such as xylitol and castor oil, peppermint oil, Examples thereof include vegetable oils such as spearmint oil, animal oils such as cod liver oil and whale oil, and liquid paraffin. Of course, carboxyvinyl polymer or the like may be used as the other material. Further, coloring agents, flavoring agents and the like can of course be used.

There are no particular restrictions on the drugs that can be added to the base for this preparation, but the main ones are as follows. Antipyretic and anti-inflammatory analgesics Indomethacin, salicylic acid, aspirin, acetaminophenone, diclofenac sodium, ibuprofen steroidal anti-inflammatory drug hydrocortisone, prednisolone, fluocinolone acetonide, hydrocortisone acetate, betamethasone acetate,
Triamcinolone acetonide Hypertension, antiarrhythmic agents Propranolol, atenolol, pindolol, quinidine sulfate, alprenolol hydrochloride antitumor agent 5-fluorouracil, 1- (2-tetrahydrofuryl) -5-fluorouracil, mitomycin C local anesthetic benzocaine, procaine, Lidocaine, tetracaine hormone estrogen, estradiol, testosterone, progesterone, prostaglandin, insulin anticoagulant heparin antibiotics tetracycline, chloramphenicol hypnotics phenobarbital, amobarbital

[0007]

The properties of the base material of the present invention can be easily controlled by appropriately changing the ratio of HPC and / or PVP to the tannin substance. That is, by changing the ratio of the two, the hardness, elasticity, solubility of the base,
The adhesiveness etc. can be changed freely. More specifically, increasing the proportion of tannin material increases hardness and decreases tackiness. Conversely, lowering the ratio of tannin substances decreases hardness and increases tackiness. More specifically, the solubility of the base of the present invention varies depending on the compounding ratio of the tannin substance. The higher the ratio of tannin substances, the lower the solubility, and the lower the ratio, the higher the solubility. Further, the tackiness of this base changes depending on the amount of tannin substance as described above, but also changes depending on the amount of PVP. That is, if the amount of PVP is increased, the tackiness increases, and if it is decreased, the tackiness decreases. Therefore, by appropriately adjusting the amounts of PVP and tannin substance, it is possible to obtain a base material suitable for the intended preparation. Thus, the pharmaceutical base of the present invention is
It is characterized in that the hardness, solubility, adhesiveness and the like can be freely changed by appropriately changing the ratio of the PPC and the PVP and the ratio of the HPC and / or the PVP and the tannin substance. As the tannin substance,
Tannic acid is most preferred. And HPC and tannic acid, HPC and PVP and tannic acid are preferable combinations. The weight ratio of HPC and / or PVP to the tannin substance is 1000: 1 to 5: 1, preferably 500: 1 to 10: 1.

[0008] Hereinafter, some methods for producing a preparation and the like using the base for preparation of the present invention will be described. A. Method for producing sustained-release preparation for oral cavity (film type) A predetermined amount of HPC and / or PVP, a tannin substance, a drug, and optionally a plasticizer and other materials are dissolved in a solvent in which these substances are soluble, and this is placed on a release film. The product is spread and dried in an appropriate amount, cut into a desired shape and size, and optionally hermetically packaged to obtain a product. B. Method for producing a support layer for an oral mucosa patch, etc. A predetermined amount of HPC and / or PVP, a tannin substance and, if necessary, a plasticizer and other materials are dissolved in a solvent in which these substances are soluble, and an appropriate amount thereof is spread on a release film. Spread and dry to form a support layer (the release film may be peeled off if necessary). In addition, in order to prepare an oral mucosa patch, a drug-containing adhesive layer may be laminated on this support layer by a usual method, and as the adhesive layer, the preparation described in A above may be laminated. C. Method for producing sustained-release tablet A predetermined amount of HPC and / or PVP, a tannin substance and, if necessary, a plasticizer and other materials are dissolved in a solvent (for example, ethanol) in which those substances are soluble, and an appropriate amount thereof is placed in a predetermined mold container. Pour and dry to obtain the product. D. Method for manufacturing wound pad of adhesive bandage Predetermined amount of HPC and / or PVP, tannin substance and, if necessary, plasticizer and other materials are dissolved in a solvent (for example, ethanol) soluble in these substances, and this is spread on a release film in an appropriate amount. It is spread and dried, and it is cut into a desired shape and size and sterilized to obtain a wound pad of a plaster.

[0009]

EXAMPLES The present invention will be described below with reference to Comparative Examples and Examples, but it goes without saying that the present invention is not limited to these. Tables 1 to 3 collectively show the combinations and contents of the agents in these Comparative Examples and Examples. In the table, H is hydroxypropylcellulose, P is polyvinylpyrrolidone, T is a tannin substance, S is a solvent, K is a plasticizer, A is a drug,
No mark indicates other optional components. Comparative Example 1 0.2 parts by weight of triamcinolone acetonide (hereinafter referred to as "TACA") and 99.8 parts by weight of hydroxypropyl cellulose (hereinafter referred to as "HPC") were added to an appropriate amount of ethanol, and the mixture was stirred and dissolved to obtain polyester. It was spread and dried on a release film to produce a film having a thickness of about 180 μm. This was cut into a circular shape with a diameter of 12 mm to obtain a mucous membrane patch for stomatitis. Comparative Example 2 TACA 0.2 parts by weight, polyvinylpyrrolidone (hereinafter referred to as "PVP") 89.8 parts by weight, and propylene glycol (hereinafter referred to as "PG") 1 in an appropriate amount of ethanol.
0.0 parts by weight was added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 180 μm. This was cut into a circular shape with a diameter of 12 mm to obtain a mucous membrane patch for stomatitis. Example 1 TACA (0.2 parts by weight), tannic acid (10.0 parts by weight) and HPC (89.8 parts by weight) were added to an appropriate amount of ethanol, and the mixture was stirred and dissolved, and this was spread and dried on a polyester release film to a thickness of about 1. A 180 μm film was produced. This was cut into a circular shape having a diameter of 12 mm to obtain a sustained-release mucous membrane patch for stomatitis. Example 2 0.2 parts by weight of TACA, 1.0 part by weight of tannic acid and 98.8 parts by weight of HPC were added to an appropriate amount of ethanol, dissolved by stirring, and spread on a polyester release film to dry to a thickness of about 2. A 180 μm film was produced. This was cut into a circular shape having a diameter of 12 mm to obtain a sustained-release mucous membrane patch for stomatitis. Example 3 0.2 parts by weight of TACA, 0.2 parts by weight of tannic acid and 99.6 parts by weight of HPC were added to an appropriate amount of ethanol, dissolved by stirring, and spread to dry on a polyester release film to a thickness of about 3. A 180 μm film was produced. This was cut into a circular shape having a diameter of 12 mm to obtain a sustained-release mucous membrane patch for stomatitis. Example 4 0.2 parts by weight of TACA, 2.0 parts by weight of gallic acid, 87.8 parts by weight of PVP and PG 10.
0 part by weight was added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 180 μm. This was cut into a circular shape having a diameter of 12 mm to obtain a sustained-release mucous membrane patch for stomatitis. Example 5 2.0 parts by weight of ibuprofen, 0.5 parts by weight of tannic acid, 70.0 parts by weight of HPC, PVP in appropriate amount of ethanol
17.5 parts by weight and 10.0 parts by weight of Macrogol 400 were added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 150 μm. This was cut into a circular shape having a diameter of 15 mm to obtain a sustained release mucous membrane patch. Example 6 5.0 parts by weight of isosorbide dinitrate, 1.0 part by weight of tannic acid, 1.0 part by weight of gallic acid, HPC in appropriate amount of ethanol
50.0 parts by weight, PVP 33.0 parts by weight and Macrogol 400 10.0 parts by weight were added, stirred and dissolved, and then spread and dried on a polyester release film to produce a film having a thickness of about 200 μm. This is 15mm in diameter
It was cut into a circular shape to obtain a transmucosal absorption type sustained release cardiotonic drug. Example 7 Propranolol hydrochloride 5.0 parts by weight, tannic acid 1.0 part by weight, HPC 50.0 parts by weight, PVP 31.0 parts by weight, carboxyvinyl polymer 3.0 parts by weight and macrogol 400 10 in appropriate amount of ethanol. 0.0 parts by weight was added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 150 μm. This was cut into a circular shape having a diameter of 15 mm to obtain a sustained release mucous membrane patch. Example 8 0.1 parts by weight of formoterol fumarate, 3.0 parts by weight of tannic acid, 30.0 parts by weight of HPC, 51.9 parts by weight of PVP, 5.0 parts by weight of ethyl cellulose in an appropriate amount of ethanol.
Parts by weight and 10.0 parts by weight of Macrogol 400 were added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 150 μm.
This was cut into a circular shape having a diameter of 12 mm to obtain a sustained release mucous membrane patch.

[0010]

[Table 1]

Comparative Example 3 95.0 parts by weight of HPC and PG were added to an appropriate amount of ethanol.
5.0 parts by weight was added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 50 μm. Separately, as an adhesive layer, add an appropriate amount of ethanol to T
ACA 0.2 parts by weight, HPC 40.0 parts by weight, PVP
49.8 parts by weight and 10.0 parts by weight of PG were added, dissolved by stirring, spread on a support layer film and dried to a thickness of about 100.
A μm adhesive layer was laminated. This was cut into a circular shape with a diameter of 12 mm to obtain a mucous membrane patch for stomatitis.

Example 9 10.0 parts by weight of tannic acid and HPC in a proper amount of ethanol
85.0 parts by weight and 5.0 parts by weight of PG were added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 50 μm. Separately, as an adhesive layer, TACA 0.2 parts by weight, HP
C 40.0 parts by weight, PVP 49.8 parts by weight and PG
10.0 parts by weight was added, and the mixture was stirred and dissolved, spread and dried on the support layer film, and an adhesive layer having a thickness of about 100 μm was laminated.
This was cut into a circular shape having a diameter of 12 mm to obtain a sustained-release mucous membrane patch for stomatitis. Example 10 3.0 parts by weight of tannic acid in an appropriate amount of ethanol, HPC
92.0 parts by weight and 5.0 parts by weight of PG were added, stirred and dissolved, and this was spread and dried on a polyester release film to produce a film having a thickness of about 50 μm. Separately, as an adhesive layer, TACA 0.2 parts by weight, HP
C 40.0 parts by weight, PVP 49.8 parts by weight and PG
10.0 parts by weight was added, and the mixture was stirred and dissolved, spread and dried on the support layer film, and an adhesive layer having a thickness of about 100 μm was laminated.
This was cut into a circular shape having a diameter of 12 mm to obtain a sustained-release mucous membrane patch for stomatitis. Example 11 0.5 part by weight of tannic acid, HPC in a proper amount of ethanol
94.5 parts by weight and 5.0 parts by weight of PG were added, stirred and dissolved, and this was spread and dried on a polyester release film to produce a film having a thickness of about 50 μm. Separately, as an adhesive layer, TACA 0.2 parts by weight, HP
C 40.0 parts by weight, PVP 49.8 parts by weight and PG
10.0 parts by weight was added, and the mixture was stirred and dissolved, spread and dried on the support layer film, and an adhesive layer having a thickness of about 100 μm was laminated.
This was cut into a circular shape having a diameter of 12 mm to obtain a sustained-release mucous membrane patch for stomatitis. Example 12 3.0 parts by weight of tannic acid and HPC in an appropriate amount of ethanol
67.0 parts by weight, ethyl cellulose 20.0 parts by weight and Macrogol 400 10.0 parts by weight were added, stirred and dissolved, and this was spread and dried on a polyester release film to produce a film having a thickness of about 50 μm. Separately, 5.0 parts by weight of isosorbide dinitrate, 40.0 parts by weight of HPC, 45.0 parts by weight of PVP and 10.0 parts by weight of Macrogol 400 were added to an appropriate amount of ethanol as an adhesive layer, and dissolved by stirring to form a film on the support layer film. Spread and dry to a thickness of about 100
A μm adhesive layer was laminated. This was cut into a circular shape with a diameter of 15 mm to obtain a transmucosal absorption type sustained release cardiotonic drug. Example 13 5.0 parts by weight of tannic acid and HPC in an appropriate amount of ethanol
85.0 parts by weight and 10.0 parts by weight of PG were added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a film having a thickness of about 50 μm. Separately, propranolol hydrochloride 5.0 was added to the appropriate amount of ethanol as an adhesive layer.
Parts by weight, 50.0 parts by weight of HPC, 35.0 parts by weight of PVP and 10.0 parts by weight of PG were added and dissolved by stirring, and spread and dried on a support layer film to laminate an adhesive layer having a thickness of about 100 μm. . This was cut into a circular shape having a diameter of 15 mm to obtain a sustained release mucous membrane patch. Example 14 Proper amount of ethanol, 10.0 parts by weight of tannic acid, HPC
80.0 parts by weight and 10.0 parts by weight of Macrogol 400 were added, stirred and dissolved, and this was spread and dried on a polyester release film to produce a film having a thickness of about 50 μm. Separately, as an adhesive layer, 0.1 part by weight of formoterol fumarate, 79.9 parts by weight of HPC in an appropriate amount of ethanol,
10.0 parts by weight of carboxyvinyl polymer and 10.0 parts by weight of Macrogol 400 were added and dissolved by stirring, and spread and dried on a support layer film to laminate an adhesive layer having a thickness of about 100 μm. This was cut into a circular shape having a diameter of 15 mm to obtain a sustained release mucous membrane patch.

[0013]

[Table 2]

Example 15 10.0 parts by weight of tannic acid and HP in appropriate amount of ethanol
50.0 parts by weight of C and 40.0 parts by weight of PVP were added and dissolved by stirring, and this was spread and dried on a polyester release film to produce a sheet having a thickness of about 300 μm. This sheet was cut into 12 mm x 24 mm to obtain a wound pad for a plaster. Separately, a butyl methacrylic acid acrylate copolymer was spread and dried on a polyvinyl chloride film having a thickness of about 50 μm as a support to manufacture an adhesive tape having a thickness of about 100 μm. Cut this adhesive tape into 20 mm x 70 mm,
Place the wound pad on the adhesive surface and sterilize to make a bandage. Example 16 To a suitable amount of ethanol, 1.0 part by weight of acrinol, 5.0 parts by weight of tannic acid and 94.0 parts by weight of HPC were added and uniformly dispersed, and this was spread and dried on a polyester release film to a thickness of about. A 300 μm sheet was produced. This sheet was cut into 12 mm x 24 mm to obtain a wound pad for a plaster. Separately, a butyl methacrylic acid acrylate copolymer was spread and dried on a polyvinyl chloride film having a thickness of about 50 μm as a support to manufacture an adhesive tape having a thickness of about 100 μm. This adhesive tape is cut into 20 mm × 70 mm, the wound pad is placed on the adhesive surface and sterilized to obtain a bandage. Example 17 0.2 parts by weight of fradiomycin sulfate, 10.0 parts by weight of tannic acid, 84.8 parts by weight of HPC and 5.0 parts by weight of PG were added to an appropriate amount of ethanol and uniformly dispersed, which was placed on a polyester film. Spread and dry to a thickness of about 500μ
m film was produced. This is 100mm × 100m
m was sterilized by cutting to obtain an external patch for burns. Example 18 3.0 parts by weight of povidone iodine, 10.0 parts by weight of tannic acid, 67.0 parts by weight of HPC and P in appropriate amount of ethanol.
20.0 parts by weight of VP was added and dissolved by stirring, and this was spread and dried on a polyester film to produce a film having a thickness of about 500 μm. This was cut and sterilized into 100 mm × 100 mm to obtain an external patch for pressure ulcer.

[0015]

[Table 3]

FIG. 1 shows the results of the main drug dissolution test of the patches obtained in Examples 1 to 3 and Comparative Example 1. Example 1
It can be seen that those of Nos. 3 to 3 are superior to those of Comparative Example 1 in the sustained release property of the main drug.

[0017]

EFFECTS OF THE INVENTION The pharmaceutical base obtained in the present invention is excellent in sustained release of the main drug and its control, and can be suitably used as it is or as a support layer of an intraoral mucosal patch while incorporating a plasticizer. It can also be used as a base for suppositories, a substitute for gauze for plasters, a skin contact surface member for patches for purulent diseases, and the like. Furthermore, during preparation, it is possible to add various drugs and plasticizers at the time of preparation, and various very good sustained release preparations (eg lozenges, buccal, oral mucosal patches, etc. Tablets etc.) can be obtained.

[Brief description of drawings]

FIG. 1 shows the results of a main drug dissolution test for the patches obtained in Examples 1 to 3 of the present invention and Comparative Example 1.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location A61K 9/70 369 383 397 47/26 C 47/38 B A61L 15/58

Claims (7)

[Claims] 1. A base for a pharmaceutical preparation obtained by dissolving hydroxypropylcellulose and / or polyvinylpyrrolidone and a tannin substance in a solvent in which these substances are soluble, and then removing the solvent. 2. The pharmaceutical base according to claim 1, wherein the tannin substance is tannic acid and / or gallic acid. 3. The pharmaceutical base according to claim 1, wherein hydroxypropyl cellulose and tannic acid are used in combination. 4. The base for pharmaceutical preparation according to claim 1, wherein hydroxypropylcellulose and polyvinylpyrrolidone are used in combination with tannic acid. 5. The pharmaceutical base according to claim 1, wherein the weight ratio of hydroxypropylcellulose and / or polyvinylpyrrolidone to the tannin substance is 1000: 1 to 5: 1. 6. The pharmaceutical base according to claim 1, which contains a plasticizer. 7. The base material for a pharmaceutical preparation according to claim 1, which further comprises an adhesive layer.