JPH0418036A - Drug composition - Google Patents

Abstract

PURPOSE:To provide a drug composition improving the dissolution degree and dissolution rate of a drug and controlling the dissolution rate by compounding an alkali-soluble chitosan, an alkali-insoluble chitosan and the slightly soluble drug. CONSTITUTION:A drug composition comprises an alkali-soluble low mol.wt. chitosan having a chitin-deacetylation degree of 90-100% and a weight-average mol.wt. of <=5000 or having a deacetylation degree of 50 to <90% and a weight- average mol.wt. of <=40000, an alkali-insoluble high mol.wt. chitosan having a weight-average mol.wt. of approximately 20X10<4> and a slightly solubly drug preferable having an average particle size of <=100mum, especially <=50mum, are mixed with each other to homogeneously disperse both the chitosan with the drug. 1 pts.wt. of the drug is compounded with 0.1-10 pts.wt. of the total amount of both the chitosans. The drug comprising the composition improves the absorption rate and amount of the slightly soluble drug into living bodies and the persistence of the drug.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a pharmaceutical composition containing alkali-soluble low-molecular-weight chitosan, alkali-insoluble high-molecular-weight chitosan, and a sparingly soluble drug.

[Conventional technology]

In general, pharmaceuticals called poorly soluble pharmaceuticals have extremely poor solubility in water, and therefore, when administered orally to living organisms, the rate of absorption is slow and the absolute amount absorbed is often small. In order to facilitate dissolution, attempts have been made to formulate salts such as hydrochloride or sodium salt, or to form water-soluble prodrugs. Also, from a pharmaceutical standpoint,
Attempts have been made to add solubilizers such as surfactants or to clathrate them with cyclodextrins.

At the crystal level, attempts have been made to pulverize or amorphize bulk powder.

However, these conventional techniques have different effective methods for each drug, so it is difficult to say that they are effective methods for all drugs.In particular, even if the absolute amount of absorption of poorly soluble drugs can be improved, it does not necessarily improve the absorption rate. The current situation is that this is not possible. However, there are many poorly soluble drugs that are expected to be fast-acting due to their pharmacological effects, and it is important to find oral preparations that are good not only in terms of absorption amount but also in terms of absorption speed. desired.

Under these circumstances, the use of various polymers to improve the absorption of poorly soluble drugs is being considered.

As a method of using high molecular weight gelatin, JP-A-57
No. 26615 describes a method of co-pulverizing a poorly soluble drug and high molecular weight gelatin. However, this method has disadvantages in that a large amount of gelatin is added to improve the absorption of poorly soluble drugs, and the production method is also limited to co-pulverization.

On the other hand, attempts have also been made to use chitin and chitosan obtained from crab and shrimp shells in preparations.

For example, in Japanese Patent Publication No. 63-28414, chitin and/or
Alternatively, chitosan and any one poorly soluble drug selected from antibiotics and antiepileptic drugs are mixed and co-pulverized to such an extent that most of the drug becomes amorphous, thereby improving the absorption rate and amount of the drug. The method is described. However, this method does not disclose low-molecular-weight chitosan, and there are problems in that mixing and co-pulverization requires a great deal of time and power, and the formulation process becomes complicated.

In addition, a method has been reported for improving the dissolution rate of kitasamycin by roll-mixing kitasamycin and various polymer compounds [Surface, 26(5) 336 (
(1988)), in which chitosan is used as an acetate solution, but its effectiveness is inferior to that of polyvinylpyrrolidone.

Therefore, in Japanese Patent Application No. 63-285566, the inventors improved the solubility and dissolution rate of poorly soluble drugs and formulated them using various formulation methods such as wet method, dry method, co-pulverization method, and spray granulation method. We are proposing a pharmaceutical composition that can This pharmaceutical composition has a weight average molecular weight of 500 to 50×103
Preferably, the composition is composed of low-molecular-weight chitosan that is soluble in neutral or alkaline water as well as acidic water, and a poorly soluble drug.

According to this drug composition, the solubility and dissolution rate of the poorly soluble drug are improved, so a fast-acting drug composition can be obtained, but the dissolution rate of the poorly soluble drug cannot be arbitrarily adjusted. In some cases, a poorly soluble drug dissolves quickly, making it impossible to obtain a long-lasting drug composition.

[Problem to be solved by the invention]

The purpose of the present invention is to solve the above problems,
It is an object of the present invention to provide a drug composition in which the water solubility and dissolution rate of various poorly soluble drugs are improved and the dissolution rate can be controlled. Another object of the present invention is to provide a pharmaceutical composition containing a poorly soluble drug that can be formulated into various forms by various formulation methods such as a wet method, a dry method, a co-pulverization method, a spray granulation method, and a gelation method.

[Means to solve the problem]

The present invention is a pharmaceutical composition characterized by containing alkali-soluble low-molecular-weight chitosan, alkali-insoluble high-molecular-weight chitosan, and a sparingly soluble drug.

The pharmaceutical composition of the present invention can be used to improve the solubility and dissolution rate of various poorly soluble drugs and other drugs, as well as to adjust the dissolution rate, and can be used to improve the absorption rate and absorption rate of these poorly soluble drugs in vivo. It can be used as a pharmaceutical or other drug composition with improved dosage and duration of efficacy.

Alkali-soluble low molecular weight chitosan used in the present invention,
and alkali-insoluble high-molecular-weight chitosan are both low-molecular-weight chitosan obtained by deacetylating natural chitin.

Among these, alkali-soluble low-molecular-weight chitosan (hereinafter referred to as alkali-soluble chitosan) has a lower molecular weight than alkali-insoluble high-molecular-weight chitosan described below, and is chitosan that dissolves in alkaline water.

In the present invention, "dissolved in alkaline water" means that when a small amount of chitosan is added to water made P118-12 with sodium hydroxide, the entire amount of chitosan is dissolved. However, the chitosan shall not contain impurities that change the pH of the liquid.

Chitosan usually has a weight average molecular weight of soo if the deacetylation rate of chitin is 90 to 100%.

Hereinafter, when the deacetylation rate is less than 50 to 90%, chitosan having a weight average molecular weight of 40,000 or less will be dissolved in alkaline water, so it is preferable to use such chitosan as the alkali-soluble chitosan.

It is not necessary to use one type of alkali-soluble chitosan alone, and a mixture of chitosan having various molecular weights can be used.

Alkali-soluble chitosan is used to increase the solubility and speed up the elution rate of poorly soluble drugs.

Note that the weight average molecular weight can be determined by gel permeation chromatography using polyethylene glycol of known molecular weight as a standard.

Alkali-insoluble high molecular weight chitosan used in the present invention (
The alkali-insoluble chitosan (hereinafter referred to as alkali-insoluble chitosan) has a larger molecular weight than the alkali-soluble chitosan.

Chitosan does not dissolve in alkaline water. Regarding the molecular weight of the alkali-insoluble chitosan, it is preferable that the weight average molecular weight is larger than that of the above-mentioned soluble chitosan, and is up to about 20×10 4 .

It is not necessary to use one type of alkali-insoluble chitosan alone, and a mixture of chitosan having various molecular weights can be used.

Alkali-insoluble chitosan is used to slow down the elution rate of poorly soluble drugs, that is, to improve the durability of drug efficacy.

The blending ratio of alkali-soluble chitosan and alkali-insoluble chitosan when blending into the pharmaceutical composition of the present invention is not particularly limited, but the larger the blending ratio of alkali-soluble chitosan, the more quickly-acting the drug will be obtained. Since a longer-lasting (slow-acting) drug can be obtained as the blending ratio is increased, the blending ratio may be selected in accordance with each poorly soluble drug used so as to obtain the desired rapid-acting and sustained action.

Chitosan, which is the raw material for alkali-soluble or insoluble chitosan, is made by extracting chitin from crab and shrimp shells, etc.
It is a polymeric substance obtained by deacetylation with an alkali. The deacetylation rate of chitin in this case is not particularly limited, but for boat fishing, a deacetylation rate of 50 to 100% is preferred. Alkali-soluble chitosan can be obtained from such chitosan by an enzymatic method in which enzymes are applied to chitosan, or by a chemical method in which hydrogen peroxide, nitrite ions, alkali, acid, etc. are added to chitosan to cleave glucoside bonds. Obtainable. Furthermore, alkali-insoluble chitosan can also be obtained by a similar method.

To obtain alkali-soluble chitosan by chemical methods,
After suspending chitosan in an alkaline solution, adding an appropriate amount of hydrogen peroxide and reacting at a constant temperature for a certain period of time to reduce the molecular weight, and adjusting the pH to 8 to 12.

Reduction is performed using a reducing agent such as NaB84, and then the solid content is removed by means such as filtration, and the resulting filtrate is desalted.

What is necessary is to perform purification such as molecular weight fractionation, drying, and powdering. The conditions for cutting chitosan and reducing its molecular weight by this method are: hydrogen peroxide concentration o, oos ~ 10% by weight, liquid temperature 20%.
~90°C and reaction time of about 30 to 500 minutes are preferred.

In order to obtain alkali-soluble chitosan by an enzymatic method, a solution or suspension of chitosan is brought into contact with chitinase or chitosanase to reduce the molecular weight, and the pH of the liquid is adjusted to 8 to 8.
12, the enzyme is inactivated by boiling, etc., solid content is removed by filtration, etc., and the resulting filtrate is soaked with N.
It may be reduced using a reducing agent such as aBH4, and then purified by salt treatment, molecular weight fractionation, etc., and dried and powdered.

When alkali-soluble chitosan is produced by the above method, alkali-insoluble chitosan may also be produced as a by-product (solid chitosan when filtered), but such alkali-insoluble chitosan is separated from the obtained reaction product. It can also be used in a state where it is mixed with alkali-soluble chitosan. When producing alkali-soluble chitosan,
If the necessary amount of alkali-insoluble chitosan is produced as a by-product, the pharmaceutical composition of the present invention can be obtained by simply blending such a mixture with a poorly soluble drug, and there is no need to further blend alkali-insoluble chitosan.

On the other hand, in order to obtain alkali-insoluble chitosan by a chemical method, chitosan is suspended in an alkaline solution, an appropriate amount of hydrogen peroxide is added, and the molecules are reduced by reacting at a certain temperature for a certain period of time to reduce the molecular weight of NaB1-1. What is necessary is just to reduce|reduce using a reducing agent, etc., and to wash the solid content obtained by filtration etc. with water, and to dry and powder it.

The conditions for cleaving chitosan and reducing its molecular weight using this method are pH 6 to 12. Preferably, the hydrogen peroxide concentration is 0.005 to 10% by weight, the liquid temperature is 20 to 90°C, and the reaction time is about 30 to 500 minutes.

In order to obtain alkali-insoluble chitosan by an enzymatic method, a solution or suspension of chitosan is brought into contact with chitinase or chitosanase to reduce the molecular weight, and the pH of the solution is adjusted to 8-8.
12, the enzyme is inactivated by boiling or the like, then reduced using a reducing agent such as NaBH4, and the solid content obtained by filtration or the like is washed with water and then powdered.

When alkali-insoluble chitosan is produced by the method described above, alkali-soluble chitosan may also be produced as a by-product. Such a mixture can be used in the same manner as the mixture obtained during the production of the alkali-soluble chitosan.

The poorly soluble drug that can be used in the present invention is exemplified by a drug that is poorly soluble in water, and is not particularly limited as long as the drug does not have a sufficient absorption rate or amount (bioavailability) into the body. Examples of such medicines include the following:

1) Hypnotic/sedative agents: For example, nitrazepam, triazolam, phenobarbital, amobarbital, etc. 2) Antiepileptic agents: For example, phenytoin, metalbital, primidone,
Clonazepam, carbamazepine, palproic acid, etc. 3) Antipyretic, analgesic and anti-inflammatory agents: flurbiprofen, mefenamic acid, ketoprofen,
ibuprofen, indomethacin, diclofenacic acid,
Phenacetin, oxyphenbutacin, phenylbutacin, sulpirin, pentazocine, piroxicam, etc. 4) #A poultices: Metarizine hydrochloride, cymenhydrinate, etc. 5) Neuropsychiatric agents: haloperidol, meprobamate, chlordiazepoxide, diazepam, oxazepam, sulpiride, etc. 6) Antispasmodics: papaverine, atropine, etomidrine, etc. 7) Cardiac drugs: digoxin, digitoxin, methyldigoxin, ubidecarenone, etc. 8) Antiarrhythmic agents: pindolol, ajmaline, zimviramide, etc. 9) Diuretics: hydrochlorothiazide, spironolactone, triamterene, furosemide, bumetanide, etc. 10) Antihypertensive agents: Nileserpine, dihydroergotoxin mesylate, prazosin hydrochloride, metoprolol, propranolol, atenolol, etc. 11) Coronary vasodilators: nitroglycerin, isosorbide nitrate, diltiazem,
Nifedipine, dipyridamole, etc. 12) Antitussives: Noscapine, salbutamol, procaterol, tulopterol, tranilast, ketotifen, etc. 13) Cerebral circulation improving agents: Nicardipine, vinpocetine, etc. 14) Antibiotics: Erythromycin, josamycin, chloramphenicol, tetracycline, rifampicin, griseofulvin etc. 15) Antihistamines nidiphenhydramine, promethacin, mequitazine, etc. 16) Steroids: triamterene, dexamethasone, betamethasone, prednisolone, danazol, methyltestosterone, chlormadinone acetate, etc.] 7) Vitamins: vitamin E, vitamin K, alfacalcidol, phytonadione, α-tocopherol nicotinate, menatetrenone, etc. 18) Others: dicoumarol, cinnarizine, clofibrate, gefarnate, cimetidine, promethacin, mercaptopurine, methotrexate, urtudesoxycholic acid,
Due to the solubility of the bulk powder, the above-mentioned poorly soluble pharmaceuticals such as dihydroergotamine mesylate have an average particle size of 100μ when ground using a wet or dry grinder.
It is desirable that the thickness be less than m, preferably less than 50 μm.

The pharmaceutical composition of the present invention can be obtained by mixing alkali-soluble chitosan, alkali-insoluble chitosan, and a sparingly soluble drug. During mixing, it is desirable to uniformly disperse both chitosans in the poorly soluble drug. The mixing method is not particularly limited, and for example, a method of simply mixing each powdered component, a method of adding an appropriate amount of a solvent such as water to each powdered component and kneading (hereinafter, the method of mixing the powdered components) (The resulting composition is referred to as a solid dispersion.), and a method in which a sparingly soluble drug is added to a solution in which chitosan is dissolved or dispersed in water. When mixing, appropriate amounts of both chitosan may be used depending on the type of M-soluble drug to be mixed. - For boat fishing, by adding 0.2 to 10 parts by weight of both chitosan to 1 part by weight of a poorly soluble drug, it is possible to improve the solubility and dissolution rate of the poorly soluble drug, and also improve the dissolution rate. can be adjusted.

The pharmaceutical composition of the present invention can be formulated and administered to humans by various methods. That is, the pharmaceutical composition of the present invention can be used as granules as is,
tablets, capsules, ointments, patches, halves, syrups,
It can also be used as a troche. These preparations contain excipients, disintegrants, and
Various additives such as lubricants can be blended.

The pharmaceutical composition of the present invention can be formulated by the following method. Tablets contain both chitosan and a poorly soluble drug in water.
The kneading method involves kneading using an acid solution or an appropriate solvent, drying, sizing, and tableting.The kneading method involves kneading both chitosan and a poorly soluble drug, drying and sizing, and then mixing various additives. It can be produced by a wet method such as a half-sided tableting method, a dry method by adjusting the amounts of both chitosan, or a co-pulverization method. Among these, it is preferable to form a solid dispersion by a wet method. It is preferable to formulate granules and capsules by a wet method as in the case of tablets, but
Depending on the case, a dry method, co-pulverization method, spray granulation method, etc. may also be employed. In addition, dosage forms such as tablets and granules may be coated for purposes such as masking.

Furthermore, poorly soluble drugs are dispersed and dissolved in both chitosan solutions,
It is also possible to formulate a formulation by adding a solution in which chitosan is precipitated or gelled, such as a polyhydric acid such as phosphoric acid, to a gelling method or forming a film-like molded product.

The preparation produced as described above has improved solubility and dissolution rate of poorly soluble drugs compared to conventional preparations, and
Because the elution rate is controlled, the drug has good bioavailability.

〔Effect of the invention〕

According to the present invention, since a layer-soluble drug is blended with alkali-soluble chitosan and alkali-insoluble chitosan, the water solubility and elution rate of the sparingly soluble drug are improved, and the drug composition has a controlled elution rate. can be obtained. Further, this pharmaceutical composition can be formulated into various forms by various formulation methods such as a wet method, a dry method, a co-pulverization method, a spray granulation method, and a gelation method. Furthermore, a pharmaceutical composition comprising the pharmaceutical composition of the present invention is a pharmaceutical product in which the rate of absorption of a poorly soluble drug into the body, the amount absorbed, and the durability of the drug's efficacy are improved.

〔Example〕

Next, examples of the present invention will be described.

Example 1 (a) Preparation of chitosan Chitosan C-0 was obtained from red snow crab by a conventional method. 600g (dry weight) of this chitosan C-0 was added to 9k of water.
360g/Q of hydrogen peroxide solution as hydrogen peroxide while stirring, keeping the pH at 8.0 and the temperature at 70°C.
was added and reacted for 5 hours to reduce the molecular weight. After reducing the molecular weight, the solid content was removed by filtration, reduced with NaBH4, and then O
Molecular weight fractionation was performed using an F membrane, desalting was performed using an ion exchange membrane, and then freeze-dried to obtain chitosan C-2 powder.

In addition, 600 g (dry weight) of the chitosan C-O was suspended in 9 kg of water, the pH was maintained at 11.0, the temperature was maintained at 70°C, and hydrogen peroxide solution was converted to 19% hydrogen peroxide while stirring.
~360g #I was added and reacted for 110-300 minutes. After the reaction, the mixture was reduced using NaBH4, filtered, washed with water, and freeze-dried to obtain powders of chitosan C-3 to C-8.

Further, acetic acid and water were added to the chitosan C-8 powder to make a 1.5% by weight acetic acid aqueous solution of chitosan C-8, and then
The pH of the solution was adjusted to 6.0 using sodium hydroxide. Chitosanase was added to this solution and reacted at 30°C for 17 hours. The pH of the solution was then adjusted to 8-9, and then boiled for 5 minutes to inactivate chitosanase, followed by Na
The mixture was reduced with BH, and filtered using a Millipore filter (manufactured by Millipore, trademark) with a pore size of 0.45 to remove solid content. The obtained filtrate was desalted using an ion exchange membrane and then freeze-dried to obtain chitosan C-1 powder.

Table 1 shows the physical properties of the C-1 to C-8 chitosan thus obtained. The weight average molecular weights of chitosan C-1 to C-8 were measured by gel permeation chromatography. That is, chitosan was dissolved using the same amount of acetic acid and an appropriate amount of water, 2.0 mu of this solution was made up to 50IIIQ with 0.2 M acetic acid-0.1 M sodium acetate buffer, and this was dissolved in TSK Ge1 manufactured by Tosoh Corporation. .3000
injected into a packed column consisting of PIJXL™ and 0.
Elution was performed with 2M acetic acid-0.1M sodium acetate buffer.

A calibration curve was determined using polyethylene glycol of known molecular weight, and the weight average molecular weight of chitosan was determined.

The deacetylation rate was determined for chitosan C-1 and C-2 from the HNMR spectrum, while for chitosan C-3 to C-8, it was determined from the colloid equivalent value at pH 4.0.

Further, a small amount of chitosan C-1 to C-8 powder was added to the alkaline water of p) 18, and after stirring, those in which chitosan powder was visible were indicated as insoluble, and those in which chitosan powder was not visible were indicated as soluble.

(b) Preparation of solid dispersion Indomethacin (hereinafter sometimes abbreviated as IMC)
and chitosan C-1 and chitosan C-3 at 1:0.5:1
．． The mixture was placed in a mortar at a weight ratio of 5:5, and about 1.2 times the total amount of water was added and kneaded for 1 hour. This mixture was air-dried for about 3 hours, then further dried under reduced pressure at room temperature for 48 hours, and sieved through a 100-mesh sieve to obtain an indomethacin/chitosan solid dispersion.

(c) Administration test The solid dispersion obtained in (b) above was filled into gelatin capsules No. 2 and administered to 4 large male peagles (body weight 10 to 11.5 kg) fasted for 24 hours at a dose of 2 mg/kg as indomethacin. A corresponding amount was administered orally with 20 liters of water. Then, three blood samples were collected from the premonitory vein using a syringe treated with heparin over time. 300 blood samples
After centrifugation at Orρm for 10 minutes, 1fflQ of plasma was collected and used for the determination of indomethacin.

The quantitative method is as follows.

To plasma 11, add 1 mR of water and pl (0.5 + nQ of 3,0 buffer)
was added, further dithyl acetate 6II+12 was added, the mixture was stirred for 15 minutes, centrifuged, and 5 mQ of ethyl acetate was collected. The internal standard solution (mefenamic acid 5
After adding 0.5 vQ (μg/mQ methanol solution) and distilling off ethyl acetate under reduced pressure, the residue was dissolved in methanol (150 μΩ) to prepare a sample solution. This sample solution IOμQ was injected into high performance liquid chromatography (ljPLc), and the indomethacin concentration was measured under the following conditions. The results of the average values of the four animals are shown in Figure 1.

(HPLC measurement conditions) Pump: Hitachi L-6000 Detector: Hitachi 655A-21UV monitor, measurement wavelength 265 nm Column: Lichrosphere 100 RP-
18 (5μm) Recorder: Hitachi D-2000, Chromatography Intigrator Mobile phase: Methanol/1% acetic acid (3:1) Flow rate: 1
mQ/min Comparative Example 1 Example 1 except that in the administration test (c) of Example 1, indomethacin powder was used alone instead of the solid dispersion, and gelatin capsule No. 0 was used as the gelatin capsule. Administration tests and indomethacin concentration measurements were conducted in the same manner as described above. The first result is the average value of the four animals.
As shown in the figure. It is also reproduced in Figure 2.

Comparative Examples 2 to 3 In the preparation (b) of the solid dispersion of Example 1, indomethacin: chitosan C-1: chitosan C-3 = 1:0.5
: 1.5 (weight ratio), indomethacin:chitosan C-1 = 1:2 (weight ratio) (Comparative Example 2), or indomethacin:chitosan C-3 = 1:2 (weight ratio) (Comparative Example 3) A solid dispersion was obtained in the same manner except that.

Comparative Example 1 was carried out in the same manner as in Comparative Example 1, except that the above solid dispersion was used instead of indomethacin powder. 4
The results of the average head values are shown in Figure 1.

From FIG. 1, it can be seen that the drug composition containing both the alkali-soluble low-molecular-weight chitosan (chitosan C-1) and the alkali-insoluble high-molecular-weight chitosan (chitosan C-3) of Example 1 has an amount of dissolved N-soluble drug. It can be seen that in addition to improving the dissolution rate, it also has slow-acting properties.

Example 2 0.33 g indomethacin, 0.5 g Chitosan C-2 of Example 1 and 0.5 g Chitosan C-2 of Example 1
6 was placed in an agate mortar, and 10 mρ of 2 volume % acetic acid was added and mixed to prepare an indomethacin suspension solution. This suspension was mixed with a 4% sodium tripolyphosphate solution (p
l+6.0)2(lomQ) with slow stirring to prepare indomethacin chitosan beads by a gelation method.The dropping rate of the suspension was approximately 60 i/min.The beads were added to sodium tripolyphosphate. 3 in solution
After soaking for an hour, it was filtered, washed with water, left to stand at room temperature for one day, and then dried under reduced pressure for another - day.

In the administration test (c) of Example 1, the administration test and indomethacin concentration were measured in the same manner as in Example 1, except that the beads were used instead of the solid dispersion and the dose was 4+og/kg. The results are shown in Figure 2.

Comparative Examples 4-7 In Example 2, 0.33 g of indomethacin, 0
．． 5g chitosan C-2 and 0.5g chitosan C-
6 instead of 0.5 g indomethacin and 1.5 g
of chitosan C-5 (comparative example 4), 0.33 g of indomethacin and 1.0 g of chitosan C-6 (comparative example 5),
0.20g (7) i:/tofitasin and 0.6
g of chitosan c-7 (comparative example 6), or 0.13 g
Indomethacin/chitosan beads were obtained in the same manner as in Example 2, except that 0.4 g of indomethacin and 0.4 g of chitosan C-8 (Comparative Example 7) were used.

Comparative Example 1 was carried out in the same manner as in Comparative Example 1, except that the above beads were used instead of indomethacin powder and the dosage was 4 rng/kg. Figure 2 shows the average value of the four animals.

From FIG. 2, it can be seen that the drug composition containing both the alkali-soluble low-molecular-weight chitosan (chitosan C-2) and the alkali-insoluble high-molecular-weight chitosan (chitosan C-6) of Example 2 has the ability to dissolve a poorly soluble drug. It can be seen that in addition to improving the dissolution rate, it also has slow-acting properties.

Reference Example 1 Solid dispersions of indomethacin (IMC) and chitosan having different mixing ratios were obtained, and an elution test of indomethacin was conducted using the solid dispersions. Chitosan C-2 obtained in chitosan preparation (a) of Example 1 was used as chitosan. The mixing ratio is 1:1 by weight of indomethacin:chitosan C-2.
．． The ratio was 1:2 or 1:3. The solid dispersion was obtained in the same manner as Preparation 11(b) of the solid dispersion of Example 1.

A dissolution test was conducted using the above solid dispersion or using indomethacin alone by the following method. − That is, a dissolution tester kept at 37°C (Toyama Sangyo Co., Ltd.)
water and 500ml of the second day liquid (acidic solution) were added to the liquid (manufactured by the company), and then the above-mentioned solid dispersion or indomethacin was added alone.
An amount equivalent to 7 mg of indomethacin was added, and a dissolution test was conducted at a paddle rotation speed of 1100 rp according to the day paddle method. 4mG of sample solution through a glass filter at regular intervals
was filtered, and the indomethacin concentration of the filtrate was measured using a spectrophotometer. The results are shown in Figure 3. In the figure, the solid dispersion is expressed in the form of "lMC-chitosan type (weight ratio)".

From Figure 3, compared to the case of indomethacin alone, the solid dispersion consisting of indomethacin and chitosan C-2 has a faster elution rate of indomethacin, and moreover, the elution rate of chitosan C-2 is faster.
It can be seen that the elution rate becomes faster when the mixing ratio of 1:2 and 1:3 and chitosan C-2 is larger than J=1.

Reference Example 2 A solid dispersion (mixing ratio: 1=2 by weight) consisting of indomethacin (IMC) and chitosan of various molecular weights was obtained, and an elution test of indomethacin was conducted using this solid dispersion. As the chitosan, chitosan C-1, chitosan C-2, chitosan C-3, chitosan C-5, or chitosan C-6 obtained in chitosan preparation (a) of Example 1 was used. A solid dispersion was obtained in the same manner as in preparation (b) of a solid dispersion in Example 1.

An elution test was conducted in the same manner as in Reference Example 1 using the above solid dispersion. The results are shown in Figure 4. In the figure, the solid dispersion is
It is written in the format of ``IMG-Chitosan type''.

From FIG. 4, it can be seen that the smaller the molecular weight, the faster the elution rate.

[Brief explanation of the drawing]

Fig. 1 is a graph showing the results of Example 1 and Comparative Examples 1 to 3, Fig. 2 is a graph showing the results of Example 2 and Comparative Examples 4 to 7, and Fig. 3 is a graph showing the results of Reference Example 1. , FIG. 4 is a graph showing the results of Reference Example 2. Agent Patent Attorney Sei Yanagihara Diagram 3 o: lMC-C-2 (1:2) Time (minutes)

Claims (1)

[Claims] (1) A pharmaceutical composition characterized by containing alkali-soluble low-molecular-weight chitosan, alkali-insoluble high-molecular-weight chitosan, and a sparingly soluble drug.