JP2006182754A - Dried product and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a dried product having an inhibitory activity against the production of a kallikrein-like substance of an extracted solution of inflammatory rabbit skin inoculated with vaccinia virus and to provide a method for producing the same. <P>SOLUTION: The method for producing the dried product of the extracted solution comprises mixing the extracted solution with a saccharide before evaporation to dryness and drying the extracted solution when the extracted solution of inflammatory rabbit skin inoculated with vaccinia virus is dried to give a solid preparation comprising the extracted solution as an active ingredient. The dried product having an inhibitory activity against the production of a kallikrein-like substance is obtained by the production method. An oral solid preparation such as tablet, etc, is produced by using the dried product. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a dried product of an inflammatory skin extract of a rabbit inoculated with vaccinia virus, and a method for producing the dried product.

The inflammatory skin extract of rabbit inoculated with vaccinia virus (hereinafter also referred to as this extract) contains a non-protein active substance extracted and separated from the inflamed skin tissue of rabbit inoculated with vaccinia virus.

Vaccinia virus-inoculated rabbit inflammation skin extract formulation (product name: Neurotropin), a drug containing this extract as an active ingredient, is a medical drug Japan Pharmaceutical Collection [2004 (27th edition), Japan Pharmaceutical Information Center, Stock As published on pages 2499-2501 of the Company Jiho], low back pain, cervical shoulder arm syndrome, symptomatic neuralgia, shoulder periarthritis, osteoarthritis, skin diseases (eczema, dermatitis, urticaria) It is a very unique formulation with a wide range of indications such as pruritus associated with it, allergic rhinitis, cold feeling / abnormal perception / pain of SMON's aftereffects, and postherpetic neuralgia. Injectables and tablets are commercially available as prescription drugs.

This extract is derived from a living body, and no single active ingredient has been identified. Therefore, the active ingredient is quantified by assaying its biological activity (titer), specifically, SART stress (repeated cold load), which is a chronic stress animal whose pain threshold is lower than that of a normal animal. A biological test method for obtaining an analgesic coefficient using a mouse has been used (“Nichi Pharmacology”, Vol. 72, No. 5, pp. 573-584, 1976). In other words, an analgesic test is performed using a SART stress mouse according to a modified Randall-Selitto method to obtain an analgesic coefficient, and a neurotropin unit (NU) is defined by an ED ₅₀ value obtained from the analgesic coefficient for a standard product. is doing. A neurotropin injection contains 1.2 units as a neurotropin unit per mL, and a neurotropin tablet contains 4.0 neurotropin units per tablet.

  In addition to the above-mentioned quantitative analgesic activity, the extract has a kallikrein-like substance production inhibitory activity (hereinafter also referred to as KPI activity) above a specified level in Japan and other countries where pharmaceutical preparations containing this extract as an active ingredient are sold. By conducting a titer test method to confirm that it has, the quality and effectiveness as a drug are more strictly guaranteed.

  Kallikrein is a proteolytic enzyme widely present in plasma and tissues of various animals, and an enzyme system called kallikrein / kinin system is known. In plasma, inactive prekallikrein is converted to active plasma kallikrein through the activation of blood coagulation factor XII, and this generated plasma kallikrein acts on high-molecular-weight kininogen in plasma, and nonapeptide of The chemical mediator bradykinin is released. Bradykinin has various actions such as powerful pain caused by sensory nerve stimulation, blood pressure lowering due to vasodilation, expression of edema due to increased capillary permeability, and plays an important role in pain, inflammation and blood flow regulation It is considered. Therefore, it has been shown that a drug having an inhibitory action on bradykinin release exhibits various medicinal effects such as analgesia, anti-inflammatory and anti-edema.

  This extract was shown to have an inhibitory action on bradykinin release (Eur. J. Pharmacol., Vol.157, No.1, p93-99, 1988). This pharmacological activity is an inhibitory action on the production of kallikrein-like substances. It was shown that it is based on. Then, a method has been developed that can quantitatively measure the ability of drugs to inhibit the production of plasma kallikrein-like substances in vitro ("Basic and Clinical", Vol. 20, No. 17, 8889-8895, 1986).

  The present invention relates to a dried product obtained in an intermediate stage for producing a final product having KPI activity as defined in the specifications and test methods of oral preparations containing an inflammatory skin extract of a rabbit inoculated with vaccinia virus as an active ingredient. The present invention relates to a method for producing a dried product. With respect to the dried product of this extract, it is only described in the following Patent Document 1 that it is solidified under reduced pressure, etc. In producing an oral preparation from this extract, a dried product having KPI activity is used. There is no prior art that discloses a specific method for manufacturing.

JP-A-53-101515

When this extract is formulated as an oral solid preparation such as a tablet, it is necessary to dry the extract. However, since the KPI activity is not observed in the dried product of the present extract obtained by usual concentration drying and the like, a solid formulation such as a tablet having KPI activity could not be produced as the final formulation.

The applicant company was forced to make long-term research and development into the oral formulation of the neurotropin injection that was manufactured and sold, and one of the difficulties at that time was obtaining a final formulation having KPI activity. Although it has been empirically found that KPI activity exists in a final preparation produced by a certain method, and development of a neurotropin tablet has been accomplished, the applicant has possessed this as know-how. As a result of systematic research on a drying method for obtaining a dried product having KPI activity with respect to the present extract, the present inventors added saccharides and mixed them before drying this extract to dry it. As a result, it was found that a dried product of the present extract having KPI activity was obtained, the optimum pH in that case, and the present invention was completed.

The present invention provides a dried product having kallikrein-like substance production inhibitory activity of an inflammatory skin extract of a rabbit inoculated with vaccinia virus, and the dried product is finally a tablet, granule, powder having KPI activity. It can be used as a raw material for producing solid preparations such as fine granules.

The present invention relates to a dried product having a kallikrein-like substance production inhibitory activity of a inflammatory skin extract of a rabbit inoculated with vaccinia virus, and a method for producing the dried product. Specifically, the present invention relates to a method for producing a dried product of the present extract, characterized in that, when the present extract is dried, saccharides are added and mixed before drying to dry. By this production method, a dried product of the present extract having KPI activity can be obtained, and it is possible to finally produce a solid preparation such as a tablet having KPI activity.

  This extract such as vaccinia virus-inoculated rabbit inflammation skin extract can be produced by the method described later, but when the obtained extract is dried, the extract is dried. It is characterized by adding saccharides before mixing and drying. Saccharides include monosaccharides such as glucose, mannose, arabinose, xylose, galactose, and sorbose, oligosaccharides such as lactose, sucrose, maltose, raffinose, and meletitol, and polysaccharides such as pullulan, dextrin, β-dextrin, and dextran. Can be mentioned. As the saccharide to be added, one of the above may be used, or two or more may be used in combination. Any polysaccharide that is insoluble in water is unsuitable for the present invention, and water-soluble polysaccharides can be used in the present invention. In addition, the water-insoluble polysaccharide corresponds to “almost insoluble” in the general rule 23 of the Japanese Pharmacopoeia (14th revision), and examples thereof include crystalline cellulose and starch.

  The amount of saccharide added can be appropriately set depending on the type of saccharide to be used, the concentration of the extract, and the like, but when lactose is used in the test extract of Example 1 below, it is preferably 0.1% by weight or more. In order to obtain a dried product of the present extract having high reproducible KPI activity, it is more preferable to add 0.5% by weight or more of lactose.

  As a drying means, concentrated drying used in usual preparation of pharmaceutical preparations can be used. For example, as a means for concentrating under mild conditions, there can be mentioned reduced-pressure drying in which moisture is distilled off and removed by digestion (35 to 45 ° C.) without heating to a very high temperature. Moreover, the excipient | filler containing the said saccharide | sugar, etc. are added and knead | mixed to this extract or its concentrate, Then, it can granulate and dry and can also obtain this granular dried product of this invention. The concentration of the extract is preferably carried out at a pH of 10 or lower, and in order to obtain a dried product of the extract having a high KPI activity, the pH is preferably adjusted to 8.5 to 9.7. preferable.

  In the present invention, the saccharide may be added to the extract from the beginning or may be added after being concentrated to some extent. However, as in the case of normal solid preparation production, it is added after drying. In some cases, KPI activity cannot be obtained in the dry product finally produced. When producing a solid preparation such as a tablet according to the present invention, it can be formulated using various additives. For example, as described in the General Formulation of the Japanese Pharmacopoeia (14th revision), The dried extract of this extract, which has been concentrated and dried with saccharides added, is granulated as it is, or is added with excipients, binders, disintegrants or other suitable additives and mixed evenly. After forming into a shape, a method of compression molding by adding a lubricant or the like, or a method of direct compression molding of a blended material can be mentioned. Further, when the extract is concentrated to some extent, additives such as the above saccharides and other excipients, binders, disintegrants and the like are added, mixed and kneaded, and granulated and dried by an appropriate method. The extract can also be tableted by a method in which the dried product is compression molded by adding a lubricant or the like. And a coloring agent, a corrigent, etc. can be added as needed, and a coating can also be given with a suitable coating agent.

The present extract used for the production of the dried product of the present invention is to inoculate rabbit skin with vaccinia virus, crush the irritated skin tissue, add the extraction solvent to remove the tissue fragment, and then remove the protein. Can be obtained by adsorbing to an adsorbent and then eluting the active ingredient.

Here, the rabbit encompasses everything belonging to the order of the rabbit eye. That is, the rabbit may be, for example, a rabbit (chira rabbit), a hare (Japanese hare), a rabbit, a snow rabbit, etc., and a rabbit that has been bred from the past and used as a domestic animal or a laboratory animal in Japan ( What is called a rabbit is easy to use.

This extract is manufactured by the following processes, for example.
(A) Rabbit skin tissue inoculated with vaccinia virus is collected, the germ tissue is crushed, and an extraction solvent such as water, phenol water, physiological saline or phenol-added glycerin water is added, followed by filtration. Alternatively, an extract (filtrate or supernatant) is obtained by centrifugation.
(B) The extract is adjusted to an acidic pH, heated and deproteinized. Next, the deproteinized solution is adjusted to be alkaline and heated, followed by filtration or centrifugation.
(C) The obtained filtrate or supernatant is acidified and adsorbed on an adsorbent such as activated carbon or kaolin.
(D) An extract from inflamed tissue inoculated with vaccinia virus can be obtained by adding an extraction solvent such as water to the adsorbent, adjusting to an alkaline pH, and eluting the adsorbed components. Thereafter, it can be appropriately adjusted to a pH near neutral to obtain a drug substance for preparation.
The above steps are described in further detail as follows.

About (a) Inflammatory skin tissue inoculated with rabbits such as rabbits with vaccinia virus is collected and crushed, and 1 to 5 times the amount of extraction solvent is added to obtain an emulsified suspension. As the extraction solvent, distilled water, physiological saline, weakly acidic to weakly basic buffer, etc. can be used. Stabilizers such as glycerin, bactericidal / preservatives such as phenol, sodium chloride, potassium chloride, chloride Salts such as magnesium may be added as appropriate. At this time, extraction can be facilitated by disrupting the cell tissue by treatment with freeze-thaw, ultrasound, cell membrane lytic enzyme, surfactant or the like.

The milky extract obtained in (b) is subjected to protein removal treatment after removing tissue fragments by filtration or centrifugation. The deproteinization operation can be carried out by a commonly known method, and includes heat treatment, treatment with a protein denaturant such as an organic solvent such as acid, base, urea, guanidine, acetone, isoelectric precipitation, salting out. Etc. can be applied. Subsequently, the insoluble protein precipitated by a usual method for removing insoluble matters, for example, filtration using filter paper (cellulose, nitrocellulose, etc.), glass filter, celite, zeit filtration plate, etc., ultrafiltration, centrifugation, etc. Remove.

The active ingredient-containing extract thus obtained for (c) is adjusted to acidity, preferably pH 3.5 to 5.5, using an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc., and the adsorption operation to the adsorbent is performed. . Examples of usable adsorbents include activated carbon, kaolin, and the like. Add the adsorbent to the extract and stir, or pass the extract through an adsorbent-filled column to add the active ingredient to the adsorbent. Can be adsorbed. When an adsorbent is added to the extract, the adsorbent can be obtained by adsorbing the active ingredient by removing the solution by filtration or centrifugation.

In order to elute (desorb) the active ingredient from the adsorbent with respect to (d), an elution solvent is added to the adsorbent, and it is eluted at room temperature or with appropriate heating or stirring, followed by normal methods such as filtration and centrifugation. Can be achieved by removing the adsorbent. As an elution solvent to be used, a basic solvent, for example, water adjusted to a basic pH, methanol, ethanol, isopropanol or the like, or an appropriate mixed solution thereof can be used, preferably water adjusted to pH 9 to 12. Can be used.

The extract (eluate) thus obtained can be appropriately prepared in a form preferable as a drug substance or pharmaceutical preparation. For example, the drug substance can be prepared by adjusting the pH of the solution to near neutral or an appropriate pH.

Below, the example of the manufacturing method of this extract is shown.
Reference example 1
The skin of healthy mature rabbits was inoculated with vaccinia virus, and the sprouted skin was exfoliated, crushed and added with phenol water. Next, this was filtered under pressure, and the resulting filtrate was adjusted to pH 5 with hydrochloric acid and then heat-treated at 90-100 ° C. for 30 minutes. The protein was removed by filtration, adjusted to pH 9 with sodium hydroxide, further heated at 90-100 ° C. for 15 minutes, and then filtered. The filtrate was adjusted to about pH 4 with hydrochloric acid, added with 2% activated carbon, stirred for 2 hours, and then centrifuged. Water was added to the collected activated carbon, pH was adjusted to 10 with sodium hydroxide, and the mixture was stirred at 60 ° C. for 1.5 hours, and then centrifuged to obtain a supernatant. Water was added again to the activated carbon precipitated by centrifugation, the pH was adjusted to 11 with sodium hydroxide, the mixture was stirred at 60 ° C. for 1.5 hours, and then centrifuged to obtain a supernatant. Both supernatants were combined and neutralized with hydrochloric acid to obtain the present extract.

Reference example 2
After vaccinia virus was inoculated and infected on the skin of healthy mature rabbits, the wrinkled skin was aseptically peeled off and cut into pieces, and then added with phenol-glycerin water and ground with a homogenizer to obtain a milky form. Next, this was filtered, and the obtained filtrate was adjusted to weak acidity (pH 4.5 to 5.5) with hydrochloric acid, and then heated at 100 ° C. and filtered. The filtrate was made weakly alkaline (pH 8.5 to 10.0) with sodium hydroxide, further heated at 100 ° C. and filtered. The filtrate was adjusted to about pH 4.5 with hydrochloric acid, added with about 1.5% activated carbon, stirred for 1 to 5 hours and then filtered. Water was added to the filtered activated carbon, the pH was adjusted to 9.4 to 10 with sodium hydroxide, the mixture was stirred for 3 to 5 hours, and then filtered. The filtrate was neutralized to near neutrality with hydrochloric acid.

Reference example 3
After inoculating and activating vaccinia virus on the skin of healthy mature rabbits, the activated skin is aseptically exfoliated, chopped into water, added with water, and ground with a homogenizer to make a milky product . Next, this was filtered under pressure, and the resulting filtrate was adjusted to pH 5.0 with hydrochloric acid and then heat-treated at 100 ° C. under flowing steam. The protein was removed by filtration, adjusted to pH 9.1 with sodium hydroxide, further heat-treated at 100 ° C., and then filtered. The filtrate was adjusted to pH 4.1 with hydrochloric acid, added with 2% activated carbon, stirred for 2 hours and then filtered. The filtrate was further filtered with 5.5% activated carbon and stirred for 2 hours. Water was added to the first activated carbon collected by filtration, the pH was adjusted to 9.9 with sodium hydroxide, and the mixture was stirred at 60 ° C. for 1.5 hours and then filtered. Water was added to the first activated carbon and the next activated carbon, adjusted to pH 10.9 with sodium hydroxide, stirred at 60 ° C. for 1.5 hours, and then filtered. The filtrates were combined and neutralized with hydrochloric acid, and then desalted by electrodialysis using a membrane having a molecular weight of 100.

Method for measuring KPI activity The inhibitory activity (KPI activity) of a test substance on plasma kallikrein-like substance production was measured according to a method described in the literature ("Basic and Clinical", Vol. 20, No. 17, 8889-8895). Page, 1986). That is, as described in detail on page 8890 of the same document, a test solution and human normal plasma diluted with physiological saline are mixed, and a kaolin suspension is added thereto to start a plasma kallikrein production reaction. After a certain time, a specific inhibitor against activated blood coagulation factor XII such as Lima bean trypsin inhibitor (LBTI) was added to stop the kallikrein production reaction, and then the produced kallikrein was converted into a chromogenic synthetic substrate (S-2302, Quantogenix). Since the synthetic substrate S-2302 liberates chromogenic p-nitroaniline by kallikrein, the amount (activity) of kallikrein produced can be measured by measuring the amount of released p-nitroaniline by absorbance at 405 nm. . The KPI activity of the test substance can be determined by determining the difference in absorbance between the group not added with the test substance (control) and the test substance addition group.

The criteria for determining whether or not the product has KPI activity can be set as appropriate. However, in the case of a neurotropin preparation, the standard is that this difference in absorbance is 0.1 or more. Is used.

Example 1
The dry matter weight of the rabbit skin inoculated vaccinia virus inoculated vaccinia virus produced according to the above Reference Example 1 was measured, and a test extract was prepared to 1 mg / mL and pH 9.5. 100 mL of the test extract was weighed and concentrated and dried under reduced pressure under digestion at about 40 ° C. Water was added to the dried product and dissolved to give a test solution of 1 mg / mL. 0.2 mL of this test solution and 0.2 mL of 0.5 M sodium chloride solution were mixed, and a measurement test was carried out according to the test procedure of the KPI activity measurement method described above. Table 1 shows an example of test results (n = 2) when the test extract is concentrated and dried as it is and when the test extract prepared by adding lactose to 1% by weight is concentrated and dried. . The control is water (hereinafter the same).

  The test system is a system in which the amount of p-nitroaniline released from the chromogenic synthetic substrate by the enzymatic activity of the produced kallikrein is measured by absorbance. In the control, a certain amount of kallikrein is produced, and the absorbance as shown in the upper part of Table 1 is measured. However, when a test substance that inhibits kallikrein production is present in the reaction system, it is measured as the production of kallikrein decreases. Absorbance is low. That is, the larger the absorbance difference from the control, the higher the KPI activity of the test substance. As shown in Table 1, the absorbance of the test solution concentrated and dried without adding lactose was not different from the control, and no KPI activity was observed. On the other hand, in the test solution concentrated and dried by adding lactose, the apparent KPI activity was measured, indicating that the dried extract of the present extract having KPI activity can be produced by the addition of lactose.

Example 2
Similar to Example 1, the case where lactose was added to the test extract and concentrated and dried was compared with the case where lactose was added after the test extract was concentrated and dried. Moreover, it measured also about the lactose solution as a blank. An example of the results is shown in Table 2. As the results shown in Table 2, only the test solution to which lactose was added and concentrated and dried showed KPI activity, and in the case where lactose was added after concentration and drying of the test extract, and in the case of a lactose-only solution, KPI activity Was not recognized at all.

Example 3
Table 3 shows the results obtained by adding additives other than lactose to the test extract and concentrating and drying in the same manner as in Example 1. Those dried by adding saccharides such as glucose (monosaccharide) or pullulan (polysaccharide) (both 1% by weight) showed KPI activity. However, excipients other than saccharides such as calcium hydrogen phosphate and water In the case of using crystalline cellulose or sorghum starch, which are insoluble polysaccharides, no KPI activity was observed.

Example 4
The results obtained in the same manner as in Example 1 using saccharides other than the saccharides described in the above Examples are shown in Table 4 (both added with 1% by weight of the test extract). The results when lactose is added at 0.5 wt% and 0.1 wt% are also shown in the same table. Table 4 summarizes the results of a plurality of tests (absorbance values of the control: 0.306 to 0.363), and shows the absorbance of the test solution and the difference in absorbance between the test solution and the control (KPI activity).

Example 5
In the same manner as in Example 1, the dry solid weight of this extract was measured, and a test extract was prepared so as to be 1 mg / mL and pH 8.8 to 9.3. 10 L of the test extract was weighed and concentrated under reduced pressure while adjusting the temperature so that it was maintained at a concentrate temperature of about 40 ° C. The mixture was concentrated to 200 mL (50 mg / mL), and about 160 g of 200 g of lactose and other excipients and disintegrants were added and kneaded and then granulated and dried. The dried granule thus obtained can be made into an oral solid preparation, for example, by adding a lubricant such as magnesium stearate and compression molding to produce a tablet.

An amount of the above dried granule calculated to contain 50 mg of the dry solid weight of this extract was taken out, 50 mL of Tris-HCl buffer (pH 8.0) was added and stirred. Subsequently, it filtered using the membrane filter and KPI activity was measured like Example 1 by making a filtrate into a test solution. In addition, a 50 mg / mL concentrated solution before addition of an excipient such as lactose was collected and measured for a test solution diluted with water to a concentration of 1 mg / mL. An example of the results is shown in Table 5. As shown in Table 5, both the concentrated liquid of the present extract and the dried granules produced by adding granules such as lactose to the concentrated liquid and kneading and drying after kneading had KPI activity.

Example 6
Table 6 shows an example of the results of tests conducted by adjusting the test extract to various pHs when lactose was added to the test extract and concentrated and dried in the same manner as in Example 1. When the pH of the test extract was 10.5, almost no KPI activity was observed, and the KPI activity of the dried product gradually decreased as it became acidic from pH 9.5.

Formulation Example 1
Dry granules of this extract were produced in the same manner as in Example 5, and tablets were produced by compression molding. That is, each component was kneaded so as to have a component amount of 4 mg of dried extract of rabbit skin inoculated with vaccinia virus, 104 mg of lactose, 40 mg of crystalline cellulose, and 20 mg of carboxymethylcellulose calcium in one tablet, and then granulated and dried. Magnesium stearate (content of 2 mg in one tablet) was added to and mixed with the dried granule, and compression-molded with a tableting machine to produce a tablet.

Formulation example 2
As in Formulation Example 1, 5 mg of vaccinia virus inoculated rabbit inflammation skin extract in 1 tablet, lactose 80 mg, calcium hydrogen phosphate 20 mg, low-substituted hydroxypropylcellulose 42 mg, hydroxypropylcellulose 2 mg, magnesium stearate 1 mg Were produced. Film-coated tablets are manufactured by spray-coating this uncoated tablet with a coating solution (hydroxypropylcellulose 40g, 10g Macrogol 6000, titanium oxide 3g, talc 5g, lake pigment 0.5g, purified water 941.5g). did.

In addition, the dried product of the present invention can be appropriately processed into oral solid preparations such as powders, granules and capsules.

The present invention provides a dried product having a kallikrein-like substance production inhibitory activity of an inflammatory skin extract of a rabbit inoculated with vaccinia virus, and the dried product can be used for formulating a solid preparation such as a tablet. it can. The method for producing a dried product of this extract having KPI activity is essentially important in the production of an oral solid preparation containing this extract as an active ingredient. The present invention is an epoch-making invention that makes it possible to provide an oral solid preparation having the extract as an active ingredient and having KPI activity. On the other hand, before the extract is dried, saccharides are added under predetermined conditions. It can be carried out by a simple operation of mixing and drying, and is an extremely economical method that does not require special additives.

Claims (27)

When drying an inflammatory skin extract of a rabbit inoculated with vaccinia virus, a saccharide is added and mixed before the extract is dried, and the mixture is dried. . Inhibition of kallikrein-like substance production of the extract, characterized in that when the inflammatory skin extract of a rabbit inoculated with vaccinia virus is dried, saccharides are added and mixed before the extract is dried, and this is dried. A method for producing a dry product having activity. The method for producing a dried product according to claim 1 or 2, wherein a saccharide is added to and mixed with an inflamed skin extract of a rabbit inoculated with vaccinia virus, and then concentrated and dried. The method for producing a dried product according to claim 1 or 2, wherein the inflammatory skin extract of a rabbit inoculated with vaccinia virus is concentrated, saccharides are added and mixed before the extract is dried and dried. The method for producing a dried product according to claim 3 or 4, wherein the extract is concentrated and dried at a pH of 10 or less. The method for producing a dried product according to claim 3 or 4, wherein the extract is concentrated and dried at pH 8.5 to 9.7.   2. One or more of glucose, mannose, arabinose, xylose, galactose, sorbose, lactose, sucrose, maltose, raffinose, meletitose, pullulan, dextrin, β-cyclodextrin and dextran are used as the saccharide. The manufacturing method of the dried material of any one of thru | or 6. A dried product of the extract obtained by drying a inflammatory skin extract of a rabbit inoculated with vaccinia virus by adding saccharides and drying the extract before the extract is dried. When drying the inflammatory skin extract of a rabbit inoculated with vaccinia virus, add sugars and mix before the extract is dried, and the extract obtained by drying this will have kallikrein-like substance production inhibitory activity. Having dry matter. The dried product according to claim 8 or 9, which is obtained by adding and mixing saccharides to the inflammatory skin extract of a rabbit inoculated with vaccinia virus, and concentrating and drying the mixture. The dried product according to claim 8 or 9, which is obtained by concentrating an extract of inflammation skin of a rabbit inoculated with vaccinia virus, adding and mixing sugars before the extract is dried, and drying the mixture. The dried product according to claim 10 or 11, wherein the extract is concentrated and dried at a pH of 10 or less. The dried product according to claim 10 or 11, wherein the extract is concentrated and dried at pH 8.5 to 9.7.   Obtained by using one or more of glucose, mannose, arabinose, xylose, galactose, sorbose, lactose, sucrose, maltose, raffinose, meletitose, pullulan, dextrin, β-cyclodextrin and dextran The dried product according to any one of claims 8 to 13.   It is obtained by concentrating an extract of inflammation skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. Dry granules of the extract.   It is obtained by concentrating an extract of inflammation skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. A dried granule having the kallikrein-like substance production inhibitory activity of the extract.   It is obtained by concentrating an extract of inflammation skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. An oral solid preparation containing the extract as an active ingredient, produced using dry granules.   It is obtained by concentrating an extract of inflammation skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. An oral solid preparation having a kallikrein-like substance production inhibitory activity, produced using dry granules, containing the extract as an active ingredient.   The oral solid preparation according to claim 17 or 18, which is a tablet.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. The manufacturing method of the oral solid formulation which contains this extract as an active ingredient by manufacturing using the dry granule obtained.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. A method for producing an oral solid preparation having a kallikrein-like substance production-inhibiting activity containing the extract as an active ingredient, by producing the resulting dry granule.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. Dried product.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. A dried product having a kallikrein-like substance production inhibitory activity.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. Dried granules.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. Dried kallikrein-like substance production inhibitory activity.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. The solid preparation for oral use which uses this extract as an active ingredient manufactured using the dry granule obtained.   It is obtained by concentrating an extract of inflammatory skin of a rabbit inoculated with vaccinia virus, adding an excipient containing at least one saccharide before the extract is dried, kneading, and granulating and drying it. An oral solid preparation having kallikrein-like substance production-inhibiting activity containing the extract as an active ingredient, which is produced by using the dried granules.