JPH02250823A - Microcapsule agent and production thereof - Google Patents

Abstract

PURPOSE:To obtain a microcapsule agent having such function as to suppress medicinal degradation by digestive enzyme by encapsulating protease inhibitor and a medicinal substance in enteric microcapsules. CONSTITUTION:An acrylic acid resin derivative such as methacrylic acid-methyl methacrylate copolymer and hydroxypropylmethyl cellulose phthalate are dissolved in a solvent (pref. ethanol), and protease inhibitor and a medicinal substance (e.g. insulin, pentagastrin) degradable or deactivable in the presence of digestive enzyme are mixed with the resultant solution in this order and agitated followed by suspension into a viscous liquid such as liquid paraffin, glycerin or vegetable oil. Thence, an aqueous solution of gelatin and/or a viscous liquid suspended therewith is(are) added to the resulting suspension to effect separation of the objective microcapsule agent. Because of being enteric, the microcapsule agent can be protected from degradation due to pepsin in the stomach, and the medicinal substance can also be protected from degradation by trypsin and chymotrypsin through the action of the protease inhibitor when said substance dissolved out at the upper part of the small intestine.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to microcapsules that enable oral administration of drugs that are degraded by digestive enzymes, such as peptide drugs, in the pharmaceutical industry, and a method for producing the same. It is.

[Prior Art and Problems] Drugs that are degraded or deactivated by digestive enzymes, such as peptide-based drugs such as insulin and pentagastrin, cannot be administered orally, and are therefore generally administered in the form of injections. However, administration of injections may cause side effects such as anaphylactic shock, ribodystrophy due to continuous or sub-injection, local allergies, and eczema.

Furthermore, in the event of excessive administration, erroneous administration, etc., treatment is extremely difficult and may not be possible. Furthermore, although there are some drugs such as insulin that are allowed to be self-injected, they generally need to be administered by a specialist such as a doctor or nurse, and for patients who require long-term administration, injections are recommended. It's also annoying.

Against this background, there is a strong need for a method to administer these drugs easily, painlessly, and reliably in a dosage form that replaces injections, and many researchers have been investigating these methods of administration. However, very few have been put into practical use.

The first problem with oral administration, which is generally considered to be the simplest and safest method, is that these drugs are degraded and inactivated by digestive enzymes.

In addition to this, there are other factors such as absorption from the intestinal tract and early pass effect in the liver, but in order to enable oral administration of these drugs, the first step is to protect them from digestive enzymes. This is essential.

Therefore, administration of preparations containing digestive enzyme inhibitors or liposome preparations are being considered, but they have not been put to practical use at present due to problems with digestive effects. Therefore, it has been desired to develop a formulation that is more inhibited from being degraded by digestive enzymes.

[Means for Solving the Problems] The present inventors have been diligently conducting research to solve the above problems, and have so far developed an orally administered drug that is inexpensive to manufacture and that dissolves the drug at a specific pH. (Jikai No. 79818 of 1988).

As a result of further research, we have found that by encapsulating drugs that are degraded or inactivated by digestive enzymes in enteric-coated microcapsules, we can prevent them from being degraded by pepsin in the stomach, and the drug can be eluted in the intestines. During the treatment, the drug was protected from degradation by tribunon and chymotrypsin by the Bu[1-tease inhibitor added to the microcapsules.
2. Furthermore, we have discovered a microcapsule formulation that can be administered orally by enhancing the absorption of drugs in the small intestine due to the absorption enhancer added to the microcapsules, and a method for producing the same, and have completed the present invention. It has come to pass.

That is, the present invention is as shown below.

(1) A drug is added to a solution of a protease inhibitor and an acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate in an organic solvent, stirred, and further suspended in a viscous liquid, and the suspension is added with an aqueous gelatin solution and/or gelatin. Microcapsules obtained by adding a viscous liquid suspended in an aqueous solution and causing precipitation.

(2) Add the drug to a solution of a protease inhibitor and an acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate in an organic solvent, stir, and suspend in a viscous liquid. A method for producing microcapsules, which comprises adding a viscous liquid in which an aqueous solution is suspended and precipitating the resulting microcapsules.

The present invention will be explained in detail below.

The drugs used in the present invention are generally applicable to drugs that are degraded or deactivated by digestive enzymes when administered orally. Specific examples include insulin, calcitonin, paprecin, oxytocin, pentagastrin, and the like.

Specific examples of organic solvents include ethanol, methanol,
Examples include propatool, hexane, ethyl ether, and 1,4-dioxane, among which ethanol is most preferred from the viewpoint of drug denaturation, solvent persistence, and safety. In addition, regarding the amount of these organic solvents to be used, there are problems such as denaturation and solubility of each drug in the solvent, so it is necessary to take these into consideration when determining the amount to be used. A nail with a ratio of about 0.5 to 20%, preferably about 1 to 10% is used.

Specific examples of acrylic acid resin derivatives include methacrylic acid/methyl methacrylate copolymers such as Eudragit L1 Eudragit S, trimethylaminoethyl methacrylate/methyl methacrylate copolymers such as Eudragit E, and Eudragit 1rts. , Said Idragi-RL
Examples include ethyl methacrylate/trimethylammonium ethyl methacrylate chloride copolymers (manufactured by Rohm Farmare 1), which may be used alone or in combination.

Specific examples of hydroquinopropyl methylcellulose phthalate include commercially available HP-50, I-I Pb0, tl
P-55S (manufactured by Shin-Etsu Chemical Co., Ltd.) can be used, and the amount of 10 to 100 times the drug, preferably 20
Use ~50 times the amount.

Specific examples of protease inhibitors include α-chymostadin, leupepsin, pepstatin (manufactured by Sigma), trypsin/chymotrypsin inhibitor (1
3B [;Bowman-Birk-1nhibito
r, manufactured by Sigma), etc., and the amount added is 10 to 200% by weight, preferably 25 to 100% by weight, based on the drug.

Furthermore, in the case of a drug that has poor absorption rate in the gastrointestinal tract, an absorption enhancer may be added as appropriate. Examples of additives intended to promote absorption include fatty acid esters such as sucrose fatty acid ester and sorbitan monopalmitate, bile acids such as glycocholic acid and sodium deoxycholate, and bile salts. In contrast, 20 to 300% by weight, preferably 50 to 100% by weight is added.

Any device such as a magnetic stirrer, chemical stirrer, or homogenizer may be used to mix the above drug, protease inhibitor, acrylic acid resin derivative, and bile salt. It is preferable to mix it with

That is, it is appropriate to dissolve the acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate in a solvent, mix the protease inhibitor and the drug in this order, and stir the mixture using the above-mentioned stirring device. If absorption enhancers are used, they are preferably added before mixing the protease inhibitor.

The mixture thus obtained is suspended in one viscous liquid. Specific examples of the viscous liquid include liquid paraffin, liquid paraffin,
Examples include silicone oil, glycerin, or vegetable oils such as sesame oil, rapeseed oil, and castor oil. Suspension can be carried out by a stirring operation using the above-mentioned apparatus.

While stirring the above suspension, add gelatin aqueous solution (
0,5 w/v%) and/or gelatin aqueous solution (0,5 w/v%) and/or gelatin aqueous solution (0,5 w/v%)
A viscous liquid containing 10% suspension of 5% w/v) is added.

At this time, it is appropriate to first add a viscous liquid in which an aqueous gelatin solution is suspended, and then add the aqueous gelatin solution.

By the above operation, the acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate dissolved in the organic solvent becomes insolubilized, and particles are precipitated. By separating this by normal fractionation operations such as suction filtration and sieving, and drying it, microcapsules having the function of suppressing the decomposition of the drug by digestive enzymes can be obtained.

Furthermore, by repeatedly carrying out the production method of the present invention using the microcapsules thus obtained as a drug in the production method of the present invention, microcapsules having multiple coatings can be obtained. Therefore, in this step, it is possible to obtain microcapsules having an outer wave film of controlled thickness made of an acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate, and having the function of suppressing the decomposition of the drug by digestive enzymes.

[Effect of the invention] According to the present invention, the following effects can be obtained.

(2) Since the microcapsules according to the present invention can elute drugs at a specific pi, drug elution can be controlled in the digestive tract where digestive enzymes that decompose or deactivate drugs are present.

(2) Since the microcapsule according to the present invention contains a protease inhibitor, it can protect the drug from being degraded by digestive enzymes such as trypsin and chymotrypsin when the drug is eluted in the upper small intestine.

(2) When the microcapsules according to the present invention contain absorption enhancers such as fatty acid esters and bile salts, absorption of the drug from the small intestine is promoted when the drug is eluted in the small intestine.

■Since it is an oral drug, it can be manufactured without special equipment like injection drugs.

■ By making it an oral drug, it is possible to reduce the annoyance and pain caused by injections for patients.

Next, the ability of microcapsules produced by the microcapsule production method of the present invention to protect drugs in various enzyme solutions will be explained using experimental examples.

Experimental Example 1 The insulin residual rate of the insulin microcapsules obtained in the examples described later in a pepsin (manufactured by Sigma) solution was measured. That is, the prepared microcapsules 0
．． pi-11 prepared by adjusting 19 to a concentration of 5 U/d of pepsin
After incubation for 1 hour at 37° C. in 10-glycine buffer of 34, the microcapsules were collected by filtration. The collected microcapsules were adjusted to pH 7.84.
The insulin concentration in this solution was measured to determine the residual percentage of insulin.

The residual rate was expressed as a percentage of the amount of insulin eluted from the same lot of microcapsules in an enzyme-free buffer using the same procedure as above as a control. The results are shown in Table 1.

Table 1 <Insulin residual rate (%) after pepsin treatment> From these results, it was confirmed that microencapsulation can prevent the decomposition of insulin by pepsin with a high probability.

Experimental Example 2 The insulin residual rate of the insulin microcapsules obtained in the examples described later in a trypsin (manufactured by Sigma) solution was measured. That is, the prepared microcapsules 0 [9] were mixed with 1800,3600 and 7200 U/
Trypsin pI adjusted to each concentration (7, 84 phosphate buffer solution 10 d, incubated for 3 hours at 37°C, and the enzyme reaction was stopped with an antagonist corresponding to trypsin (Trypsin Inhibitor Cosigma)) After that, the residual rate was calculated from the insulin concentration in the solution.

The residual rate was determined in the same manner as in Experimental Example 1. This result is the second
Shown in the table.

After incubating at 37° C. for 3 hours in 10IIIi of a pt17.84 phosphate buffer solution of α-chymotrypsin shown in Table 2 and stopping the enzyme reaction with I3[31, the residual rate was calculated from the insulin concentration in the solution. The IIJcrY ratio was determined in the same manner as in Experimental Example 1. The results are shown in Table 3.

Table 3 Insulin residual rate (%) after treatment with α-chymotlib
)〉From this result, 3600.1 for trypsin
It was confirmed that at a concentration of 800 U/111, the microcapsules obtained in Example 5 could protect insulin from yeast degradation by 50% or more.

Experimental Example 3 α of insulin microcapsules obtained in the example below
- The insulin residual rate with respect to the chymotrypsin (manufactured by Sigma) solution was measured. That is, 0.1 g of the prepared microcapsules were added to 6,7.13.3.26.5.5
3. The microcapsules obtained in Example 5 contained approximately 50% insulin in a solution with an α-chymotrypsin concentration of 6.70/d, and the microcapsules obtained in Example 6 contained approximately 50% of insulin. Microcapsules are α
- It was confirmed that a solution of chymotribunone with a low density of 26.5 U/d could also protect insulin from enzymatic degradation by about 85%.

Experimental Example 4 The residual rate of pentagastrin after the pentagastrin microcapsules obtained in the examples described later was treated with a trypsin solution was measured. That is, the prepared microcapsules 0
．． I) H7,841J of trypsin adjusted to a concentration of 1800,3600°7200U/d:/acid buffer solution 10! After incubating for 3 hours at 37° C. in 1ll1 and stopping the enzyme reaction with BBI, the residual rate was calculated from the concentration of pentagastrin in the solution. The residual rate was determined in the same manner as in Experimental Example I. The results are shown in Table 4.

Table 4 The results confirm that the microcapsules obtained in Example 7 can significantly protect pentagastrin from enzymatic degradation by trypsin.

The present invention will be described in more detail below with reference to Examples of the production of microcapsules according to the present invention, but the present invention is not limited thereto.

Example 1 Methacrylic acid/methyl methacrylate copolymer [trade name: Eudragit 5100, manufactured by Rohm Pharma Co., Ltd.]
Insulin [manufactured by Sigma] o, sg dissolved in 5 g of dilute hydrochloric acid solution was added to the solution of 14 g of BBIO, 39 dissolved in 5 g of diluted hydrochloric acid solution, which was stirred with a magnetic stirrer (Mardistirrer-HS 48P manufactured by Iuchi Seieido Co., Ltd.). and stir for 5 minutes.

Immediately apply this solution 209 to silicone oil [product name: Silicone KF96, manufactured by Shin-Etsu Silicone Co., Ltd.] 3009.
and suspended. Stirring was performed using an experimental stirrer (manufactured by Tokyo Rika Kikai Co., Ltd., Chemistryler B-100). While stirring this suspension, add silicone oil Gelatin aqueous solution (0.5 w/v%) at 307
Each was added three times.

After continuing stirring for 10 minutes, the stirring was stopped, the mixture was allowed to stand, and the separated aqueous layer was collected using a branch funnel, and the aqueous layer was filtered with suction to remove particles in the aqueous layer.

The particles were dried at 20-25° C. and 110011H for 24 hours to obtain 4.09 microcapsules. This microcapsule contains 2% insulin.
BBI is contained at 2%.

Example 2 Same as Example 1 except that the amount of BB[ added was 0.159 (Thus, insulin microcapsules were prepared. As a result, insulin was 2% and BBI was 1%). Microcapsules containing 4.09
I got it.

Example 3 Insulin microcapsules were prepared in the same manner as in Example 3, except that BBI was not added. As a result, microcapsules 4.01 containing 2% insulin and no BBI were obtained.

Example 4 Methacrylic acid/methyl methacrylate copolymer [Eudragit L100 Co149, BBIO139 were added to ethanol 409 and stirred. To the stirred solution, insulin 0.69 dissolved in 5 g of dilute hydrochloric acid solution was added and stirred for 5 minutes. . This solution 209 was immediately poured into liquid paraffin (manufactured by Kanto Kagaku Co., Ltd.) 30°9 and suspended. Stirring was performed using a magnetic stirrer. While stirring this suspension, add 10% gelatin aqueous solution (0.5 w/v%).
After adding liquid paraffin 1009 suspended at a concentration of
txQ was added three times each. After continuing stirring for 10 minutes, as a coating operation, a 20 W/W % ethanol solution of the above methacrylic acid/methyl methacrylate copolymer 259 suspended in 120 g of liquid paraffin was added to this solution, and 3 After stirring for a minute, gelatin aqueous solution (0,
5w/v%) to 50I! i was added twice. After repeating this coating operation twice, continue stirring for 10 minutes, stop stirring, leave to stand, collect the separated aqueous layer with a branch funnel, and filter the aqueous layer with suction. The particles inside were collected by filtration. The particles were heated at 15-20°C110+v
*I(g) for 18 hours to obtain microcapsules 9.09 with an additional coating on the outer layer. These microcapsules contain 2% insulin and 1% BBr.

Example 5 Insulin microcapsules were prepared in the same manner as in Example 4 except that the amount of BBL added was 0.69. This reduces insulin by 2%
Microcapsules 9.09 containing 2% of BB[ were obtained.

Example 6 Methacrylic acid/methyl methacrylate copolymer [Eudragit L100] +59, glycocholic acid [Sigma Co0.39, BB I O, 3f, Chymostatin [
Insulin 0.3o, A9 manufactured by Sigma Corporation was added to 40g of ethanol and stirred, and then dissolved in dilute hydrochloric acid solution 59.
Add 6g and stir for 5 minutes.

20 g of this solution was immediately poured into 300 g of liquid paraffin and suspended. Stirring was performed using a magnetic cooler. Add gelatin aqueous solution (0.5 w/v%) to this suspension.
After adding 100 g of liquid paraffin suspended at a concentration of 10%, add gelatin aqueous solution (0.5 w/v%) every 3 minutes.
) was injected 3 times to 30.71".

IO minutes] IJ1 After continuing stirring, as a coating operation, a 20 m/W% ethanol solution 259 of the above methacrylic acid/methyl methacrylate copolymer suspended in liquid paraffin 1209 was added to this liquid. After stirring for 3 minutes, add 5% gelatin aqueous solution (0.5 w/v%).
0- was added twice.

After repeating this operation twice, continue stirring for 10 minutes, then stop stirring, leave to stand, collect the separated aqueous layer with a branch funnel, and then filter the aqueous layer with suction. The particles were collected by filtration. The particles were heated at 10-15°C, IOzzI-1
Microcapsules 10.09 were obtained by drying for 18 hours at 100 g for 18 hours to obtain microcapsules 10.09 with an additional coating on the outer layer. This microcapsule contains
Insulin is 2%, BBI is 1%, chymostatin is 1%.
% and 1% glycocholic acid.

Example 7 Hydroxypropyl methylcellulose phthalate [Product name: I-IP-55, Co149 manufactured by Shin-Etsu Chemical Co., Ltd.
, BBIo, 39 was added to ethanol 409, and to the stirred solution was added 0.
Strong ammonia water diluted with 69 [manufactured by Kanto Kagaku Co., Ltd.] (
1-=100) and stir for 5 minutes. Immediately add this solution 209 to liquid paraffin 309
9 and suspended. Stirring was performed using a magnetic stirrer. While stirring this suspension, liquid paraffin + OOG in which gelatin aqueous solution (0.5 w/v%) was suspended at a concentration of 10% was added, and then gelatin aqueous solution (0.5 v/v%) was added every 3 minutes. ) was added three times in 307 portions each.

After continuing stirring for 10 minutes, as a coating operation, a 20 w/w % ethanol solution of the above methacrylic acid/methyl methacrylate copolymer 257 suspended in 120 g of liquid paraffin was added to this liquid, After stirring for 3 minutes, gelatin aqueous solution (0.5 v/v%) was added twice at 50 d each. After repeating this coating operation twice, continue stirring for 10 minutes, stop stirring, leave to stand, separate the aqueous layer using a separatory funnel, and then filter this aqueous layer with suction. Particles in the liquid were collected by filtration. The particles were freeze-dried ('c4! -40℃, vacuum degree 0, I
mttrl (g, shelf temperature 20°C) to obtain 9.0 g of microcapsules further coated on the outer layer. The microcapsules contain 2% pentagastrin, [8+
It contains about 1%.

Example 8 The microcapsules obtained in Example 7 were filled into No. 0 gelatin capsules (200xy in 1 capsule) to obtain hard capsules containing 41 g of pentagastrin.

Claims (2)

[Claims] (1) A drug is added to a solution of a protease inhibitor and an acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate in an organic solvent, stirred, and further suspended in a viscous liquid, and the suspension is added with an aqueous gelatin solution and/or gelatin. Microcapsules obtained by adding a viscous liquid suspended in an aqueous solution and causing precipitation. (2) A drug is added to a solution of a protease inhibitor and an acrylic acid resin derivative or hydroxypropyl methyl cellulose phthalate in an organic solvent, stirred, and further suspended in a viscous liquid, and the suspension is added with an aqueous gelatin solution and/or gelatin. A method for producing microcapsules, which comprises adding a viscous liquid in which an aqueous solution is suspended and precipitating the resulting microcapsules.