JPH01311015A - Drug composition - Google Patents

Abstract

PURPOSE:To obtain a drug composition for mucous membrane especially suitable for suppository, etc., having low organism irritant by using polyvinyl alcohol as a main component, gelling by mixing of polyhydric alcohol, drug and water, then increasing water holding property. CONSTITUTION:5-40wt.% polyvinyl alcohol is mixed with 5-25wt.% 3-4C polyhydric alcohol, 0.01-60wt.% drug and 10-89wt.% water, heated and dissolved to obtain a uniform and viscous solution. Next, said solution is charged in a mold for shaping and gelled at below room temperature to afford the aimed composition. Said polyvinyl alcohol has >=95mol% saponified degree and >=500 average degree of polymerization. Although not especially restricted as drug, the composition is widely used for anesthetic drug, antiepileptics, sleeping and sedative agent, antiulcer agent or resolution and analgesic agent, etc.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides polyvinyl alcohol (hereinafter abbreviated as PVA)
The present invention relates to the composition of a pharmaceutical product whose main base material is a pharmaceutical composition, and particularly to a pharmaceutical composition suitable for mucosal preparations such as suppositories.

(Prior Art) Many methods for gelling PVA are known. Broadly speaking, they are as follows: (1) A method of gelling by adding a so-called crosslinking agent and performing a chemical reaction A to form covalent bonds or ionic bonds.

(≧) A method in which gelation is achieved by irradiating radiation without adding any additives or by freezing and thawing operations.

It is classified into two types.

In the case of (2), examples of additives include alkaline aqueous solution,
Metal salts, amino compounds, phenols, boric acids, organosilicon compounds, aldehydes, carboxylic acids, olefins, etc. are known. However, among the gels obtained by adding these, some have poor mechanical strength, and others lack stability over time. Furthermore, when applying the gel obtained by adding these to a living body as a medicine, the greatest fear is that the additives leaked from the gel or their reaction products may be irritating to the living body.

Since most of the above additives have harmful effects on living organisms, it is extremely difficult to actually apply them as pharmaceuticals.

(Problems to be Solved by the Invention) In the case of (1) above, since PVA itself has extremely low irritation to living organisms, the possibility of its application as a pharmaceutical base is extremely high. However, in order to perform the gelation method of PVA by radiation irradiation (Japanese Patent Application Laid-Open No. 50-55647, gelation method by γ-ray irradiation generated from cobalt-60), a radiation irradiation facility is required, and the gel obtained by this method is is a soft gel with poor mechanical strength, and its production requires relatively large costs.

On the other hand, a low-temperature crystallization method using freezing and thawing operations (Unexamined Japanese Patent Publication No. 1983
9-56446, JP 60-177066) and the freezing/partial vacuum drying method (JP 57-130543), the PVA hydrogels have sufficient mechanical strength as pharmaceutical bases and are resistant to living organisms. It has the excellent properties of being extremely hypoallergenic and being able to be manufactured easily and at low cost. However, when a drug is prepared using gel as a base using this method, there is a significant loss of moisture from the preparation, and therefore extremely strict packaging is required to prevent this and to store it stably for a long period of time. Although this is essential, it is technically very difficult to detect minute pinholes if they exist in such packaging.

From this point of view, it is an object of the present invention to obtain a pharmaceutical composition that uses PVA as its main base material and that can be stably supplied to medical sites even in commonly used packaging. It is something.

(Means for Solving the Problems) In order to solve the above-mentioned problems, the present inventors have developed a polyhydric alcohol, that is, propylene glycol, which enhances the water retention of the preparation and has extremely low biostimulant properties.

Glycerin, 1,3-butylene glycol, etc. were incorporated into the composition.

PVA used in the present invention requires a saponification degree of 95 mol% or more, preferably 97 mol% or more.If the saponification degree is lower than this, for example 85 mol% or less, the mechanical strength of the resulting gel will be poor, The purpose of the invention is not achieved, and
The average degree of polymerization must be at least 1400; anything less than that will result in only an extremely soft gel. However, when preparing the composition by mixing two or more types of PVA with different average degrees of polymerization, If one of them has an average degree of polymerization of 1,800 or more, the other has a PV with an average degree of polymerization of 500 to 1,000.
It is also possible to use A.

In the present invention, these PVAs are used in an amount of 5 to 40% by weight of the entire formulation. If PVA is dissolved more than once, the PVA may not be completely dissolved, or even if it is dissolved, the viscosity thereof may exceed 10,000 cP, resulting in operational inconveniences as described below. In particular, when using PVA with an average degree of polymerization of 14 (10 or more), the concentration is preferably 10 to 25% by weight.Also, when using a mixture of PVA with an average degree of polymerization of 500 to 1800 or more, , each concentration is 1
-25% by weight and 10-25 It% are preferred.

The polyhydric alcohol used in the present invention is one or more polyhydric alcohols simultaneously selected from the group having 3 to 4 carbon chains, such as propylene glycol, glycerin, and 1,3-butylene glycol. 1 alcohol
It is preferable to add these polyhydric alcohols so that the sum of their weight percentages is 5 to 25%.If the addition rate of these polyhydric alcohols is less than 5% by weight, sufficient water retention properties of the preparation cannot be obtained. If the addition rate is 80% by weight or more,
PVA does not dissolve uniformly, and it is 25-80% by weight.
In this case, even if PVA is uniformly dissolved, when the resulting gel is stored for a long period of time, -
- Unfavorable as it causes partial solid phase/liquid phase separation and liquid seeps onto the gel surface.

The above composition, i.e., the necessary amount of drug (0.1 to 60
% by weight) and then add water to make it 100% and dissolve by heating to obtain a uniform viscous solution. If the drug is not completely dissolved, it is made into a uniformly dispersed suspension or emulsion (hereinafter abbreviated as drug-containing sol, including the above-mentioned viscous solution). Also, if the drug to be added is unstable at high temperatures,
The ingredients from these compositions except for the drug are heated and dissolved in advance, and after the temperature drops to an appropriate temperature, the drug is added and mixed.
Obtain a homogeneous drug-containing sol. This drug-containing sol is injected into a desired mold, frozen at a temperature below the freezing point,
Thaw gradually at 1-10°C. The mechanical strength of the resulting gel increases as the number of times this freezing/thawing operation is performed increases, but it is usually preferably about 1 to 3 times.

The target drug of the present invention is not particularly limited, including its pharmaceutically acceptable salts. For example, the target drug can be the drugs listed below. Former anesthetics such as ketamine hydrochloride and trobelitol, antiepileptic drugs such as primitone, phenytoin, and carbamazepine, flurazepam, triazolam,
Sleeping sedatives such as phenoharbital sodium, anti-ulcer drugs such as cimetidine and ranitidine hydrochloride, anti-inflammatory analgesics such as diclozenaf sodium, piroxicam, ketoprofen, and pranoprofen, gout drugs such as allopurinol and penzturoman, dibekacin sulfate, etc. Antibiotics such as amikacin sulfate, minocycline hydrochloride, and fosfomycin, analgesics such as thimepicium bromide, antiparkinsonian drugs such as levodopa, amantadine hydrochloride, and piperidine hydrochloride, bronchodilators such as salbutamol sulfate, tulofterol hydrochloride, and ketotifen fumarate, captopril, etc. antihypertensive drugs, coronary vasodilators such as nifedipine, diltiazem hydrochloride, dipyrytamol, isosorbitate nitrate, peripheral vasodilators such as nicardipine hydrochloride, inenprodil tartrate, pindolol, a!
β-receptor blockers such as acid propranolol, peptide pharmaceuticals such as elcatonin and insulin, antineoplastic drugs such as fluorouracil, tigafur, and ancitabine hydrochloride, antiemetics such as tonberitone, and adrenocortical hormones such as dexamethacin sodium phosphate. etc.

(Function) The composition obtained by the present invention contains polyhydric alcohols such as propylene glycol and glycerin as described above. These polyhydric alcohols have extremely low toxicity to living organisms, have appropriate wettability, good solubility and emulsifying properties, and are inexpensive.
It is a well-known fact that it is widely used as an ingredient in cosmetics such as toothpastes, lotions, creams, and shampoos, and pharmaceuticals, without giving specific examples. Among these properties, especially its moderate wettability,
It is believed that this greatly contributes to the water retention property of the pharmaceutical composition according to the present invention.

(Examples) Next, the pharmaceutical composition of the present invention will be explained with reference to Examples, but the present invention is not limited to these Examples. Note that the unit % used in the following text means weight percentage unless otherwise specified.

(Example 1) Preparation of RG-1 Ketoprofen 3.15g, 5% sodium hydroxide aqueous solution 9.95g (1.0 equivalent to ketoprofen), distilled water 40.50g, propylene glycol 12
．． 0Og, and PVA (Gohsenol [F] N11-26 manufactured by Nippon Gosei Kagaku Kogyo ■, degree of saponification 99.4 mol% or more, average degree of polymerization 2,600) 14.40g to 200g
In addition to the sprinkled glass beaker, in the autocrate (
The mixture was heated at 110° C., t, Z atm. for 40 minutes. After the internal pressure became equal to normal pressure, stirring was performed while hot to obtain a uniform drug-containing sol. Add this to a commercially available suppository mold (■Kanae, polyvinyl chloride, 1.90g mold).
After dispensing 0 portions, the opening of the mold was simply sealed with adhesive tape, and the sol was frozen by leaving it at -10°C for 10 hours, and then leaving it at 4°C for 14 hours. By repeating the freezing and thawing operation for one more time, the ketoprofen 7 in the drug was thawed.
RG-1 containing 1 g of 5Il and 15% of brobylene glycol was obtained.

(Example 2) Preparation of RG-2 PVA (Go-1?/-4@N)l-25) 27.
7g, chrycerin 23.1g, distilled water 99.2g for 30
The mixture was added to a glass beaker with a diameter of 0.0 mm and heated in an autoclave (110° C., 1.2 atm) for 40 minutes. After the internal pressure became equal to normal pressure, stirring was performed while hot to obtain a uniform PVA viscous solution. 2.11 g of diclozenafnafnatrim was added to 77.9 g of this viscous solution and stirred while hot to obtain a uniform drug-containing sol. As described in Example 1, 1.
By dispensing 90 g each and performing the same freezing and thawing procedure twice, 50 g of diclozenaf sodium in each drug was obtained.
and RG-2 containing 15% glycerin, respectively, were obtained.

(Example 3) Preparation of RG-3 PVA (Gose/-L@N) l-20, degree of saponification 98
．． 5 to 99.4 mol%): 11.0 g, 1. 23.1g of coftylene glycol, 99.2g of distilled water, 30
The mixture was added to a glass beaker and heated in an autoclave (110°C, 11, 2 atm) for 40 minutes. After the internal pressure becomes equal to normal pressure, stir while hot to create a uniform PVA.
A viscous solution was obtained. 2.53 g of diltiazem hydrochloride was added to 77.5 g of this viscous solution and stirred while hot to obtain a uniform drug-containing sol. As described in Example 1, <, 1.90
By dispensing 60 mg of diltiazem hydrochloride in 1.3 g, the same freezing and thawing procedure was performed twice.
-RG each containing 10% butylene glycol-
I got 3.

(Example 4) Preparation of RG-4 By the same operation as in Example 2, PVA (Gohsenol@
NH-26) 27.7g, propylene glycol 20
．． 1 g of distilled water and 102.2 g of distilled water were heated in an autoclave, and 2.11 g of dibekacin sulfate was added to 77.9 g of the resulting PVA viscous solution and stirred while hot to obtain a uniform drug-containing sol. As described in Example 1, this was dispensed into 1.90 g portions and the same freezing and thawing operations were carried out twice.
By applying twice, gibelicin sulfate SOIIg in one drug
, RG containing 13% propylene glycol, respectively.
-4 was obtained.

(Example 5) Made of tlI from RG-5 By the same operation as in Example 2, 20.3 g of PVA (Gohsenol@NH-26), 2 propylene glycol
0.4 g and 59.3 g of distilled water were heated in an autoclave, and 21.1 g of fosfomycin sodium was added to 58.9 g of the resulting PVA viscous solution and stirred while hot to obtain a homogeneous drug-containing sol. . Example 1
Dispense 1.90 g each and freeze and freeze in the same manner as described in
By carrying out the thawing operation twice, RG-5 containing 500 mg of fosfomycin sodium and 15% propylene glycol in each preparation was obtained.

(Example 6) Preparation of RG-6 By the same operation as in Example 1, saltutamol sulfate 0.
253g, distilled water 47.50g, propylene glycol 12.00g, PVA (Gohsenol@N11-2
6) 8.00g and PVA (Gose/-le@NL-
O5, degree of saponification 98.5 mol% or more E, average degree of polymerization 500
) 12.00 g was heat-treated in an autoclave and stirred while hot to obtain a uniform drug-containing sol. Dispense this into 1.90g portions in the same way, freeze and thaw twice.
By applying twice, 6 g of salbutamol sulfate per drug
, RG containing 15% propylene glycol, respectively.
-6 was obtained.

(Example 7) Preparation of RG-7 By the same operation as in Example 1, 8.42 g of tegafur,
33.60 g of 5% aqueous sodium hydroxide solution, 11.58 g of distilled water, 12.00 g of l,:l-butylene glycol, and PVA (Gohsenol@NH-18
．． Saponification degree 98.0-99.0 mol%, average polymerization degree 1,
800) 14.40 g was heat-treated in an autoclave and stirred while hot to obtain a uniform drug-containing sol. By dispensing 1.90 g of this in the same way and performing the freezing and thawing operations twice, 20 tegafur in one drug was obtained.
RG-7 each containing 15% of 0H11,3-butylene glycol was obtained.

(Example 8) Preparation of RG-8 Ketotifen fumarate 4
2mg, distilled water 53.56g, propylene glycol lO, 40g and PVA (Gohsenol N+)-1
8) 16.00 g was heat-treated in an autoclave and stirred while hot to obtain a uniform drug-containing sol. By dispensing 1.90 g of this in the same manner and subjecting it to freezing and thawing twice, 1.90 g of ketotiphen fumarate was added to each drug. RG-8 containing 13% of OIIg and 13% of propylene glycol was obtained.

(Example 9) Preparation of RG-9 By the same operation as in Example 1, 2.11 g of phenoharbital sodium, 51.49 g of distilled water, 10.40 g of glycerin and PVA (Gosenol@N1l-
18) A uniform drug-containing sol was obtained by heat-treating 15.00 g in an autoclave and stirring while hot. This was similarly dispensed into 1.90 g portions and subjected to freezing and thawing operations twice to obtain RG-9 containing 13% of phenoharbital sodium SOB and 13% of glycerin, respectively.

(Example 10) Preparation of RG-10 By the same operation as in Example 1, 1.26 g of Tonbelitone
, tartaric acid 0.444g, distilled water 51.90g, 1
．． 12.00g of 3-butylene glycol and PVA (
Gosenol@NH-26) 14.40 g was heat-treated in an autoclave and stirred while hot to obtain a uniform drug-containing vine. This was similarly dispensed into 1.90 g portions and subjected to freezing and thawing operations twice to obtain RG-10 containing 30 mg of tonbelitone and 15% of 1.3-butylene glycol in each preparation.

(Example 11) Preparation of RG-11 Dexamethacin phosphate 0
．． 842g, distilled water 52.76g, chrycerin 12.
OOg and PVA (Gohsenol@NH-26) 14
．． 40 g was heat-treated in an autoclave and stirred while hot to obtain a uniform drug-containing sol. By dispensing 1.90 g of this in the same way and performing freezing and thawing twice, each drug contains 20 mg of dexamethacin phosphate,
RG-11 each containing 15% of chrycerin was obtained.

(Comparative Example 1) Preparation of RG-12 By the same operation as in Example 1, 3.15% of ketoprofen
g, 5% sodium hydroxide 9.95g, distilled water 48g
．． 50g and PVA (Go(1'/-le@Nll-2
6) Heat-treat 14.40g in an autoclave,
A homogeneous drug-containing sol was obtained by stirring while hot. Dispense this into 1.90g portions in the same way, freeze and thaw twice.
By applying once, 75 mg of ketoprofen in one tablet
RG-12 containing the following was obtained.

(Comparative Example 2) Preparation of RG-13 By the same operation as in Example 1, 3.15
g, 9.95 g of 5% sodium hydroxide, 28.g of distilled water.
50g, propylene glycol 24.00g and PVA
(Gosenol NH-25) 14.40 g was heat-treated in an autoclave and stirred while hot to obtain a uniform drug-containing sol. Similarly, add 1.90g
After dispensing, the opening of the half-open mold was simply sealed with adhesive tape, and the sol was frozen by leaving it at -50°C for 10 hours, and then by leaving it at 4°C for 14 hours. I unzipped this. By repeating this freezing/thawing operation for one more step, RG-13 containing 75 mg of ketoprofen and 30% of propylene glycol in each preparation was obtained.

(Test example) Change in composition weight in open system RG-1,
One each of 3, 6, 12, and 13 (4 cases per group)
After weighing, the sample was placed on a glass petri dish (inner diameter 3 ha) and left under 250C192% relative humidity without packaging. The weights of these samples were measured after 0.5, 1 and 2 months, and expressed as percentage change (%) with respect to the weight before standing, and summarized in Table 1. In addition, for compositions other than RG-12, only liquid oozed out onto the petri dish while standing under the above conditions, so the weight change rate after wiping this off was calculated as (
). The numerical values in the table are expressed as the standard error of the average value of 4 cases.

(Margins below) Table 1 (Effects) Weight change of the compositions when the four compositions in the examples of the present invention and Comparative Examples RG-12 and RG-13 were left under the conditions of 25°C and 92% relative humidity. The results of observation over time are shown in Cloth-1. Even when left under such relatively mild conditions, RG-1, which does not contain polyhydric alcohol,
2, a weight reduction of 47% in 0.5 months and 65% in 2 months was observed.

On the other hand, the weight changes of the four types of compositions according to the present invention ranged from 12 to +
It was within 6%. Furthermore, by leaving it for 2 months, 4 to 1
A leaching of 1% liquid was observed, which provides adequate lubrication when administering the formulation to the anus. In addition, comparative example RG-1 containing 30% propylene glycol
3, the weight increased by about 40% during the storage period, probably due to moisture absorption, etc.

The leaching of liquid from the composition was also significant, with approximately 30% of its weight leaching out over a period of 2 months.

As described above, the present invention not only improves the water retention of the obtained composition, but also shows a range of the amount of polyhydric alcohol added that does not cause solid phase/liquid phase separation in one composition, As a result, the storage stability of the obtained pharmaceutical composition could be improved.

Claims (1)

[Scope of Claims] 1) A pharmaceutical composition for mucosal application, characterized in that a uniform viscous solution consisting of polyvinyl alcohol, polyhydric alcohol, drug, and water is filled into a mold and gelled at room temperature or below. . 2) The pharmaceutical composition according to claim 1, wherein the polyvinyl alcohol has a degree of saponification of 95 mol% or more and an average degree of polymerization of 500 or more. 3) Polyvinyl alcohol has a weight percentage of 5
The pharmaceutical composition according to claim 1, containing ~40%. 4) The pharmaceutical composition according to claim 1, wherein the polyhydric alcohol is selected from the group having 3 to 4 carbon chains and contains 5 to 25% by weight of the polyhydric alcohol. . 5) The pharmaceutical composition according to claim 1, wherein the drug is contained in a weight percentage of 0.01 to 60%. 6) The pharmaceutical composition according to claim 1, which contains water in a weight percentage of 10 to 89%.