JP5232725B2 - Method for producing royal jelly having blood pressure lowering action - Google Patents

Description

  The present invention relates to a method for producing a royal jelly having a blood pressure lowering action, and a royal jelly composition and a blood pressure lowering agent containing the royal jelly obtained by the method.

  Royal jelly is a milky white paste-like substance secreted by the pharyngeal glands of young worker bees, and its components are abundant in amino acids including essential amino acids and are composed of high-quality proteins. In addition, it contains trace components such as vitamins, minerals and carbohydrates. Examples of vitamins include vitamin B1, vitamin B2, vitamin B6, niacin, pantothenic acid, vitamin A, vitamin C, and vitamin E, which are effective in promoting growth and preventing aging. Minerals include potassium, magnesium, calcium, copper, iron, phosphorus and the like. Examples of carbohydrates include glucose and fructose. Furthermore, acetylcholine-like substances, organic acids (such as 10-hydroxydecenoic acid), fats, and protein-like antibacterial substances such as leuricin are included.

  As described above, royal jelly contains various nutritional components and has many known effects such as antibacterial action, immune enhancement action, anti-inflammatory action, anti-aging action, prevention / treatment action for menopause, and anticancer action. ing.

  On the other hand, the number of patients with hypertension among lifestyle-related diseases is estimated to be 20 million in Japan over 30 years old, and high blood pressure has an aspect called current national disease. Hypertension is a risk factor for various chronic diseases, and is known to induce vascular disorders such as cerebrovascular disorders and myocardial infarction. As the population ages more and more in the future, the number of hypertensives is expected to increase, and improvement of hypertension or prevention of the onset is an issue (Non-patent Document 1).

Angiotensin converting enzyme (hereinafter sometimes abbreviated as ACE) converts angiotensin I into angiotensin II, which is a blood pressure increasing substance, and degrades bradykinin that has a blood pressure lowering action, thereby increasing blood pressure. Therefore, if there is a substance that inhibits ACE (ACE inhibitor), blood pressure can be lowered, and it is expected to be effective in preventing or treating hypertension.
As an ACE inhibitor that lowers blood pressure by suppressing ACE activity, for example, captopril has been developed and used as a pharmaceutical product.

  On the other hand, in the food field, milk casein (Non-patent document 2), wakame protein (patent document 1, non-patent document 3), bonito (non-patent document 4, non-patent document 5), sardine (non-patent document 6), etc. Numerous foods containing ACE inhibitors such as enzymatic degradation products, fermented milk (Non-patent Document 7), and Bunaharitake extract (Non-patent Document 8) are commercially available.

Attempts have been made to obtain ACE inhibitors by hydrolyzing royal jelly using the digestive enzymes of animals such as trypsin and proteolytic enzymes derived from Bacillus subtilis (Patent Document 2, Patent Document 3, Non-Patent Document) Reference 9). Furthermore, peptides such as isoleucine-tyrosine, valine-tyrosine, and isoleucine-valine-tyrosine are known as components involved in lowering blood pressure when royal jelly is hydrolyzed using a proteolytic enzyme derived from Bacillus subtilis (non-patented). Reference 10). However, trypsin used to digest royal jelly is an animal-derived digestive enzyme, and royal jelly hydrolyzed with trypsin has a problem that it is difficult to completely rule out contamination of animal-derived infectious substances, making it safer. An ACE inhibitor derived from royal jelly is desired. Furthermore, royal jelly hydrolyzed with a proteolytic enzyme derived from Bacillus subtilis has a problem of low ACE inhibitory activity, and an ACE inhibitor having higher ACE inhibitory activity is desired.
As described above, different proteolytic enzymes are used for various food materials. This is probably because the protein contained in the food material is different, and the optimal proteolytic enzyme for each protein is selected.

JP 2002-138100 A JP-A-4-279597 JP 2006-28065 A

Hiroyuki Fujita et al., Pharmacology and Treatment Vol.25 (8), 147 (2155) -151 (2159) (1997) Maruyama S., Agr. Biol. Chem., 51, 1581 (1987) Health Sciences, 20, 82-90 (2004) Yokoyama K., Biosci. Biotech. Biochem., 56, 1541 (1992) Fujita H. et al., J. Food Sci., 65, 564 (2000) Eiji Seki et al., Japanese Journal of Agricultural Chemistry, Vol. 69 (No. 8), 1013-1020 (1995) Yamamoto N. et al., J Dairy Sci, 77, 917-922 (1994) Yuji Sakamoto et al., Applied Pharmacology 61 (4/5), 221-229 (2001) Hiroe Maruyama et al., Journal of Japan Society for Food Science and Technology, Volume 50 (7), 310-315 (2003) Tokunaga K. et al., Bio. Pharm. Bull., 27 (2), 189-192 (2004)

  An object of the present invention is to provide a new technique capable of obtaining a royal jelly having a blood pressure lowering action, particularly an angiotensin converting enzyme inhibitory action.

  As a result of intensive studies, the present inventors have found that the above-mentioned problem can be solved by causing a proteolytic enzyme derived from Paenibacillus polymyxa to act on royal jelly, thereby completing the present invention.

That is, the present invention
1. a method for producing a royal jelly having a blood pressure lowering action, comprising a step of allowing a proteolytic enzyme derived from Paenibacillus polymyxa to act on royal jelly,
2. The method for producing the royal jelly, wherein the blood pressure lowering action is an angiotensin converting enzyme inhibitory action,
3. The method for producing any of the above-mentioned royal jelly, wherein the royal jelly is a substantially fully digested royal jelly,
4. A royal jelly composition containing the royal jelly obtained by any one of the above production methods, and
5. An antihypertensive agent containing royal jelly obtained by any one of the above production methods,
Consists of.

  According to the present invention, a royal jelly having an antihypertensive action, particularly an angiotensin converting enzyme inhibitory action, can be produced by a safer and simpler method. Can be provided.

  The royal jelly of the present invention is produced by allowing a proteolytic enzyme derived from Paenibacillus polymyxa to act.

  Examples of the country of origin of royal jelly include Japan, China, Taiwan, Thailand, Brazil, European countries, Oceania countries, the United States, etc. Royal jelly of any country of origin may be used. Further, a plurality of royal jelly of the country of origin may be appropriately mixed and used. The royal jelly is preferably a liquid, and when lyophilized royal jelly is used, it can be used after being dissolved in purified water, tap water, or an appropriate buffer. The frozen royal jelly can be used after being thawed.

  Further, the royal jelly may be one to which processing such as heating, centrifugation, alcohol extraction, filtration, freeze drying or hot air drying, and various nutrients are added.

  The proteolytic enzyme derived from Paenibacillus polymixer that acts on royal jelly is obtained by culturing Paenibacillus polymixer, and may be a culture solution or a purified product. Further, the proteolytic enzyme derived from Paenibacillus polymixer may be obtained by gene recombination, and may be further modified with, for example, sugar or polyethylene glycol. Furthermore, the cultured Paenibacillus polymixer may be added to royal jelly and fermented under certain conditions. The Paenibacillus polymixer is also called a Bacillus polymyxa.

  The proteolytic enzyme derived from Paenibacillus polymixer may be allowed to act alone on royal jelly, and further, the proteolytic enzyme derived from Paenibacillus polymixer and other proteolytic enzymes may be used together to act on royal jelly. The necessary amount of the proteolytic enzyme may be allowed to act on the royal jelly at once, or the necessary amount may be acted on the royal jelly in two or more times. In addition, when two or more types of proteolytic enzymes are allowed to act on royal jelly in combination with the proteolytic enzyme derived from Paenibacillus polymixer and other proteolytic enzymes, each proteolytic enzyme may be allowed to act on royal jelly at the same time. Well, you may work separately with the royal jelly.

  The solid content concentration of the royal jelly after mixing with the proteolytic enzyme derived from Paenibacillus polymixer can be 0.1 to 30 W / W%, preferably 1 to 15 W / W%, more preferably 4 to 10 W / W%. Can be mentioned. Here, for example, 10 W / W% means that 10 g of a dried product is obtained when 100 g of royal jelly is dried by freeze drying or the like.

  The processing conditions of royal jelly with a proteolytic enzyme derived from Paenibacillus polymixer, such as the processing time, pH, and temperature, are not particularly limited as long as the target antihypertensive substance is produced, and the stability of royal jelly and It can be appropriately set in consideration of the stability and reactivity of the proteolytic enzyme derived from Paenibacillus polymixer. In order to obtain a royal jelly having a high blood pressure lowering action, it is preferable that the royal jelly is substantially completely digested by a proteolytic enzyme derived from Paenibacillus polymixer to sufficiently produce a blood pressure lowering substance. Here, substantially complete digestion means that a protein contained in royal jelly is hydrolyzed by a proteolytic enzyme and hydrolyzed into a fragment that is no longer substantially hydrolyzed by the enzyme. Such a condition is such that a proteolytic enzyme derived from Paenibacillus polymixer is allowed to act on royal jelly under various conditions, and the resulting blood jelly is measured for its blood pressure lowering action, preferably ACE inhibitory action, by a known method to obtain a high action Can be determined by selecting.

  The time for which the paenibacillus polymixer-derived proteolytic enzyme and royal jelly are allowed to act is not particularly limited as long as the target antihypertensive substance is produced, but is preferably several hours to 10 days, preferably 10 hours to 24 hours. There was no change in the production of hypotensive substances even after 24 hours of reaction.

  The pH when paenibacillus polymixer-derived proteolytic enzyme is allowed to act on royal jelly is not particularly limited as long as the target blood pressure-lowering substance is produced, but is pH 3-11, preferably pH 5-11, more preferably pH 7. ~ 10 is suitable.

  The temperature at which paenibacillus polymixer-derived proteolytic enzyme is allowed to act on royal jelly is not particularly limited as long as it is a temperature at which a blood pressure-lowering substance is produced, but 30 ° C to 80 ° C, preferably 30 ° C to 60 ° C is appropriate. .

  While the proteolytic enzyme derived from Paenibacillus polymixer is allowed to react with the royal jelly, it may be left still, and may be further shaken or stirred.

  The production of the royal jelly of the present invention generally includes a step of inactivating the proteolytic enzyme derived from the above Paenibacillus polymixer. The method for inactivating the proteolytic enzyme derived from Paenibacillus polymixer may be to inactivate the proteolytic enzyme derived from Paenibacillus polymixer to the extent that there is no problem as a food. Examples of the inactivation method include a method of inactivation by heating, a method of inactivation using a drug, and a method of removing a proteolytic enzyme derived from Paenibacillus polymixer by filtration, and these methods may be used alone, Two or more types may be combined. Preferably, the proteolytic enzyme derived from Paenibacillus polymixer is inactivated by heating. It is appropriate to heat at a heating temperature of 60 ° C or higher, preferably 80 ° C or higher, more preferably 90 ° C or higher. Furthermore, when a food sterilization step is necessary, it may be combined with a step of inactivating the proteolytic enzyme derived from the Paenibacillus polymixer.

  Furthermore, when a proteolytic enzyme derived from Paenibacillus polymixer is allowed to act on royal jelly, a stabilizer or reaction accelerator for the proteolytic enzyme derived from Paenibacillus polymixer may be added.

  The royal jelly produced by the action of a proteolytic enzyme derived from Paenibacillus polymixer is a royal jelly having a blood pressure lowering action, preferably an ACE inhibitory action. The royal jelly is preferably a royal jelly that has been substantially completely digested with a proteolytic enzyme derived from Paenibacillus polymixer.

  The ACE inhibitor may be purified by treating the royal jelly of the present invention with various types of chromatography. Examples of the purification method include gel filtration chromatography, ion exchange chromatography, affinity chromatography, hydrophobic chromatography, reverse phase chromatography, normal phase chromatography, ultrafiltration, electrophoresis and the like. These can be used for purification alone or in combination.

  Gel filtration chromatography includes a carrier for gel filtration chromatography that can separate proteins having various molecular weights, and a carrier for gel filtration chromatography that can separate proteins having a molecular weight of about 10,000 or less is preferable. Examples of ion exchange groups used in ion exchange chromatography include anion exchangers and cation exchangers. Examples of anion exchangers include diethylaminoethyl groups (DEAE groups) and quaternary aminoethyl groups (QAEs). ) And the like. Examples of the cation exchanger include a carboxymethyl (CM) group and a sulfopropyl (SP) group. Examples of the carrier used in the hydrophobic chromatography include a carrier having a butyl group (Butyl group), an ethyl group (Ethyl group), and a phenyl group (Phenyl group) bound thereto. Examples of the carrier used for the reverse phase chromatography include octadecyl group (C18), and a carrier to which C30, C8, C4, etc. having different alkyl group length from octadecyl group are bonded. Examples of the carrier used for normal phase chromatography include silica gel, as well as a carrier bonded with a cyanopropyl group, a functional group having a diol structure, an aminopropyl group, a polyamine, and the like.

  The royal jelly of the present invention can be used as a blood pressure lowering agent by performing purification using the above-described chromatography or the like. Moreover, it can provide as a royal jelly composition by adding various components to the blood pressure-lowering royal jelly of this invention or its refined product. Examples of the various components include foods, sugars, lipids, emulsifiers, thickeners, seasonings, fragrances, sourness adjusters, preservatives, fruit juices, fragrances, various nutritional components, and the like, and do not impair the effects of the present invention. Can be used in Moreover, various components may be used independently and may be used in mixture of 2 or more types. Examples of sugars include sucrose, isomerized sugar, glucose, fructose, palatinose, trehalose, lactose, xylose and the like. Examples of emulsifiers include sucrose fatty acid esters, glycerin fatty acid esters, and lecithin. Examples of the thickener include carrageenan, gum arabic, xanthan gum, guar gum, pectin, locust bean gum thickener starch, gellan gum and the like. Examples of the sourness adjuster include citric acid, lactic acid, malic acid, fumaric acid, gluconic acid, tartaric acid and the like. Examples of the preservative include benzoic acid and its salt, sorbic acid and its salt, paraben, sodium sulfite, pectin degradation product, glycine and the like. Examples of the fruit juice include tomato juice, plum juice, apple juice, lemon juice, orange juice, and berry juice. Examples of the fragrances include spices such as herbs and spices, fruit fragrances, and fragrances such as vanilla. In addition, other preferable nutrients include vitamins such as vitamin D and minerals such as calcium, magnesium, iron, manganese, and zinc.

  The royal jelly, royal jelly composition or antihypertensive agent of the present invention can also be used as a food prepared by adding and blending them. Specific examples of such foods include, for example, beverages, confectionery, candy, gum, bread, livestock meat products, dairy products, retort foods, instant foods, frozen foods, jelly-like foods, beekeeping products, pickles, seasonings And so on. These foods are also useful as so-called health foods, functional foods, foods for specified health use, functional nutritional foods, dietary supplements, supplements and the like. Moreover, granule, powder, tablet, capsule, chewable, drink, jelly, paste, grain etc. can be mentioned as the shape as those foods.

  Examples of the present invention will be described below, but the present invention is not limited to these examples.

  Screening for a proteolytic enzyme suitable for treatment to obtain a royal jelly having a blood pressure lowering effect was performed. Table 1 shows the proteolytic enzymes used in the tests and their origins. The blood pressure lowering effect was measured using ACE inhibitory activity as an index.

  Specifically, first, about 50 mL of purified water was added to 10 g of 30 W / W% royal jelly, pH was adjusted by adding HCl or NaOH, purified water was added to 60 mL, and a royal jelly dilution was prepared. Add the proteolytic enzymes shown in Table 1 and react at 40 ° C for 14 hours, then heat in boiling water for 30 minutes to inactivate the proteolytic enzymes, allow to cool, and centrifuge at 3,000 rpm for 10 minutes. I got Qing. The supernatant was measured for ACE inhibitory activity. ACE inhibitory activity was performed by the method shown below. The pH of the royal jelly diluent is pH 7.0 for the proteolytic enzymes shown in (1) and (4) of Table 1, and the proteolytic enzymes shown in (2), (3) and (5) of Table 1. Was adjusted to pH 3.0.

  The amount of proteolytic enzyme added is 614 mg of P6141-5G (from Paenibacillus polymixer) per 100 mL of royal jelly diluent, and other proteolytic enzymes are measured according to the [Proteolytic enzyme activity measurement method] shown below. The same activity (ΔA660) as -5G (from Paenibacillus polymixer) was added to the royal jelly diluent.

[Method for measuring ACE inhibitory activity]
<Preparation of borate buffer>
450 mM 50 mM Na ₂ B ₄ O ₇ and 550 mL 220 mM H ₃ BO ₄ were mixed to prepare a borate buffer solution having a pH of 8.3.
<Sample preparation>
The supernatant was diluted 10 times with borate buffer (pH 8.3) to prepare a sample.
<Preparation of substrate solution>
After dissolving 170 mg of Bz-Gly-His-Leu · H ₂ O (molecular weight: 447.49, manufactured by Peptide Laboratories) and 1.78 g of NaCl in about 30 mL of borate buffer, adjust to pH 8.3 with 1N NaOH, and then borate buffer The volume was made up to 50 mL with the solution to obtain a substrate solution.
<Preparation of ACE solution>
Angiotensin converting enzyme (from rabbit lung, Sigma) was dissolved in borate buffer to make a 60 mU / mL solution as an ACE solution.
<Method for measuring ACE inhibitory activity>
(1) Measurement of inhibitory activity 30 μL of the sample and 250 μL of the substrate solution were mixed and allowed to stand at 37 ° C. for 5 minutes. After leaving for 5 minutes, 100 μL of ACE solution was added, and after reacting at 37 ° C. for 30 minutes, 250 μL of 1N HCl was added to stop the reaction. After stopping the reaction, 1.5 mL of ethyl acetate was added and stirred vigorously for 1 minute. Next, the mixture was centrifuged at 3,000 rpm for 10 minutes, and 0.5 mL of the upper ethyl acetate layer was collected and evaporated to dryness with a centrifugal evaporator (40 ° C., 1.5 hours). After evaporating to dryness, 2 mL of purified water was added and dissolved, and the absorbance at 228 nm was measured. The absorbance at this time is A.
(2) Measurement of blank 30 μL of the sample and 250 μL of the substrate solution were mixed and left at 37 ° C. for 35 minutes. After standing for 35 minutes, 250 μL of 1N HCl was added, and then 100 μL of ACE solution was added. Further, 1.5 mL of ethyl acetate was added and stirred vigorously for 1 minute. Next, the mixture was centrifuged at 3,000 rpm for 10 minutes, and 0.5 mL of the upper ethyl acetate layer was collected and evaporated to dryness with a centrifugal evaporator (40 ° C., 1.5 hours). After evaporating to dryness, 2 mL of purified water was added and dissolved, and the absorbance at 228 nm was measured. The absorbance at this time is B.
(3) Measurement of control (1) In the measurement of inhibitory activity, the same operation was performed using a borate buffer instead of the sample, and the absorbance at 228 nm was measured. The absorbance at this time is C. Further, in the above (2) blank measurement, the same operation was performed using a borate buffer instead of the sample, and the absorbance at 228 nm was measured. The absorbance at this time is D.
(4) Calculation The ACE inhibitory activity was determined by the following formula.
ACE residual activity (%) = (A−B) × 100 / (C−D)
ACE inhibitory activity (%) = 100-ACE residual activity (%)

[Proteolytic enzyme activity measurement method]
(1) Preparation of Substrate Solution Preparation of substrate solution A: 0.6 g of casein (Hamalstein formulation) was suspended in 75 mL of 100 mM lactic acid buffer (pH 3.0) and dissolved by heating in boiling water. After standing to cool, the pH was adjusted to 3.0, and the volume was adjusted to 100 mL to obtain substrate solution A.
Preparation of substrate solution B: 0.6 g of casein (Hamalstein formulation) was suspended in 75 mL of 100 mM bis-trispropane buffer (pH 7.0) and dissolved by heating in boiling water. After standing to cool, the pH was adjusted to 7.0, and the volume was adjusted to 100 mL to obtain substrate solution B.
In addition, the substrate solution A was used for the proteolytic enzyme activity measurement of (2), (3) and (5) shown in Table 1, and the proteolytic enzyme activity measurement of (1) and (4) shown in Table 1 was used. Used substrate solution B. Furthermore, when proteolytic enzyme activity is high and dilution is required, 100 mM lactate buffer (pH 3.0) is used for the proteolytic enzyme activity measurement of (2), (3) and (5) shown in Table 1, The proteolytic enzyme activities (1) and (4) shown in Table 1 were diluted using 100 mM bis-trispropane buffer (pH 7.0).
(2) Measurement of proteolytic enzyme activity
After 2 mL of the substrate solution was allowed to stand at 40 ° C. for 5 minutes, 0.4 mL of the sample solution was added, and after reacting at 40 ° C. for 30 minutes, 2 mL of 0.44 M trichloroacetic acid solution was added to stop the reaction. The reaction was stopped for 10 minutes at room temperature, followed by filtration with No. 2 filter paper (Advantech Toyo). To 0.5 mL of the filtrate, 1.25 mL of a 0.55 M Na ₂ CO ₃ solution and 0.25 mL of a phenol reagent diluted 3-fold with purified water were added, and the mixture was allowed to stand at 37 ° C. for 30 minutes, and then the absorbance at 660 nm was measured. The absorbance at this time is A.
(3) Blank measurement
The measurement was performed in the same manner as in the above (2) measurement of proteolytic enzyme activity except that 0.4 mL of the sample solution was added after adding 2 mL of 0.44 M trichloroacetic acid solution. The absorbance at 660 nm is B.
(4) Calculation ΔA660 was determined by the following formula. In the following formula, D means the dilution rate.
ΔA660 = (A−B) × D

  Table 2 shows the ACE inhibitory activity of royal jelly treated with each proteolytic enzyme. Among the proteolytic enzymes tested, the lyophilized product of P6141-5G (from Paenibacillus polymixer) treated royal jelly showed better ACE inhibitory activity.

  In addition, the proteolytic enzyme activity of P6141-5G (derived from Paenibacillus polymixer) added with 594 mg per 100 mL of royal jelly diluted was “A-B” when diluted 100-fold with 100 mM bis-trispropane buffer (pH 7.0) The value of was 0.25 (ΔA660 = 25).

  The IC50 of P6141-5G (derived from Paenibacillus polymixer) and protease N “Amano” G (produced by Amano Enzyme, Inc., derived from Bacillus subtilis) were compared.

  Approximately 50 mL of purified water was added to 10 g of 30 W / W% royal jelly, and HCl or NaOH was added to adjust to pH 7.0, and then purified water was added to 60 mL to prepare a royal jelly dilution. P6141-5G (from Paenibacillus polymixer) was added 594 mg per 100 mL of royal jelly diluent, reacted at 40 ° C for 14 hours, heated in boiling water for 30 minutes to deactivate the proteolytic enzyme, allowed to cool, and then freeze-dried And a lyophilized product was obtained. Protease N “Amano” G was also measured for proteolytic enzyme activity according to [Proteolytic enzyme activity measurement method] shown in Example 1, and the same proteolytic enzyme activity (ΔA660) added to the royal jelly diluent was used. P6141-5G The same operation as in (Paenibacillus polymixer) was performed to prepare a freeze-dried product. The activity of protease N “Amano” G was measured using the substrate solution B shown in [Proteolytic enzyme activity measurement method].

  The lyophilized product was dissolved in a borate buffer, and IC50 was measured. IC50 was measured according to [Method for measuring ACE inhibitory activity] in Example 1.

  The results are shown in Table 3. As shown in Table 3, the freeze-dried product of P6141-5G (derived from Paenibacillus polymixer) lyophilized product had a lower IC50 value and a higher inhibitory activity of ACE. IC50 shown in Table 3 indicates the concentration of the sample.

  The P6141-5G (from Paenibacillus polymixer) -treated royal jelly obtained in Example 2 was subjected to a single-dose blood pressure lowering medicinal effect test. After pre-breeding spontaneously hypertensive rats (SHR) for 3 weeks, suspended the lyophilized product to 2.5 mg / mL in 14-week-old SHR (6 mice per group, male), 10 mL was orally administered per 1 kg of body weight (25 mg / kg). As a result, the average blood pressure in the lyophilized product administration group 6 hours after administration was 181 mmHg. On the other hand, the average blood pressure of the subject group was 208 mmHg, and the blood pressure-lowering effect was significantly (p <0.05) by oral administration of the lyophilized product. The subject group was administered 10 mL of purified water.

  The royal jelly having a blood pressure lowering effect obtained by the present invention can be suitably used for food and drink as a royal jelly composition or a blood pressure lowering agent, and can be particularly suitably used for health foods and the like.

Claims (5)

A method for producing a royal jelly having a blood pressure lowering action, comprising a step of allowing a proteolytic enzyme derived from Paenibacillus polymyxa to act on royal jelly. 2. The method for producing a royal jelly according to claim 1, wherein the blood pressure lowering action is an angiotensin converting enzyme inhibitory action. 3. The method for producing a royal jelly according to claim 1, wherein the royal jelly is a royal jelly that has been substantially completely digested. 4. A royal jelly composition containing the royal jelly obtained by the production method according to any one of claims 1 to 3. 4. An antihypertensive agent comprising a royal jelly obtained by the production method according to any one of claims 1 to 3.