Non-oily matrix plant soft capsule and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and provides a non-oily matrix plant soft capsule and a preparation method thereof. The plant soft capsule consists of a capsule material and a content, the content is composed of active pharmaceutical ingredients and a matrix; the matrix is prepared from the following raw materials: PEG-400 (Polyethylene Glycol), hydroxypropyl maltodextrin and water; the capsule material is prepared from the following raw materials: carrageenan, galactose, mannose and water. The soft capsule disclosed by the invention has the characteristics of fast disintegration and rupture, high stability and the like under the combined action of the capsule wall material and the matrix, and meanwhile, the stability of active ingredients which are easy to oxidize can also be improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and provides a non-oily matrix plant soft capsule and a preparation method thereof. BACKGROUND

[0002] Soft capsules (also known as gelatin capsules) are a kind of packaging of capsules, commonly used in medicines or health foods, and are a kind of capsule prepared by sealing liquid medicines or liquid-solid medicines in soft capsule materials. The capsule wall of a general soft capsule is made of gelatin, which has poor adhesion and toughness and is prone to oxidative crosslinking. A plasticizer such as glycerol is usually added to overcome this problem. For the capsule core matrix material, an oily matrix such as soybean oil, medium-chain triglyceride (MCT), a non-water suspension medium such as PEG, and a beeswax thickening system are usually selected.

[0003] For example, Chinese invention patent CN102225055B discloses a soft capsule shell formula, which uses gelatin as the wall material and glycerol and sorbitol as plasticizers. By adjusting the ratio of the two, the moisture retention performance of sorbitol is ensured, and problems such as softening, deformation, adhesion, leakage, etc. of the capsule shell due to excessive moisture are avoided. The use of mixed plasticizers ensures the stability of the soft capsule. However, when the matrix material has a water absorption effect on the capsule material, it causes the migration of moisture in the capsule shell to the content, resulting in the re-crystallization and precipitation of some dissolved hydrophobic drugs during the production process, and the continuous penetration of water-soluble drugs in the content to the capsule wall, which causes the capsule shell to fade, become hard, and affect the disintegration time, thereby reducing the drug utilization and affecting the full play of the drug effect.

[0004] Chinese invention patent application CN118845690A discloses a non-oily matrix plant soft capsule and a preparation method thereof. The content matrix of the non-oily matrix plant soft capsule includes PEG-400, low-molecular-weight hydroxypropyl maltodextrin, a potassium ion-containing salt, and purified water. It is found in the implementation process that after adding low-molecular-weight hydroxypropyl maltodextrin, potassium ions, and purified water to PEG-400, the corrosion of the matrix to the capsule material mainly composed of pre-gelatinized hydroxypropyl starch and carrageenan is significantly reduced, the long-term stability of the capsule is significantly improved, and the problems of in-vitro disintegration or content leakage of the capsule can be significantly improved. However, it is found in the preparation process that carrageenan has poor solubility at low temperatures and needs to be homogenized by a special process (such as heating). However, high temperature may damage the structure of the pre-gelatinized starch, causing a decrease in viscosity or failure of the gel. The preparation process control is relatively strict. In addition, insufficient dissolution of carrageenan may affect the subsequent disintegration efficiency, and the formation of a high-strength, low-elasticity gel in the presence of potassium ions may delay disintegration if the ion concentration is too high or the formula design is improper.

[0005] Therefore, it is necessary to further optimize the matrix and capsule material to ensure that the matrix has low corrosiveness to the capsule material and the soft capsule has high stability under the premise of relatively simple process. SUMMARY

[0006] In view of the problems in the prior art, the present application provides a non-oily matrix plant soft capsule and a preparation method thereof.

[0007] The technical scheme of the present application is as follows. In a first aspect, the present application provides a non-oily matrix plant soft capsule composed of a capsule material and contents; the contents are composed of a pharmaceutical active ingredient and a matrix; the preparation raw materials of the matrix include PEG-400, hydroxypropyl maltodextrin and water; and the preparation raw materials of the capsule material include carrageenan, galactose, mannose and water.

[0008] Preferably, the preparation raw materials of the matrix include PEG-400 100 parts, hydroxypropyl maltodextrin 0.1-20 parts and water 0.1-5 parts by weight.

[0009] More preferably, the preparation raw materials of the matrix include PEG-400 100 parts, hydroxypropyl maltodextrin 1-10 parts and water 0.5-2 parts by weight.

[0010] Further preferably, the preparation raw materials of the matrix include PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 part by weight.

[0011] In some embodiments of the present application, the preparation of the hydroxypropyl maltodextrin includes but is not limited to the following methods: Take 100 parts of hydroxypropyl starch, add 200 parts of deionized water, add 0.2 parts of concentrated sulfuric acid, stir uniformly, heat to 90℃, stir for 30-120 minutes, stop heating, and add sodium hydroxide to adjust pH to 6.5-7.5 to terminate the reaction; then hot air dry at 80℃ until the moisture content is 5-10%, and the hydroxypropyl maltodextrin (DE value of 2-20) is obtained.

[0012] The pharmaceutical active ingredient is soluble in PEG-400, including vitamins and nutritional supplements, traditional Chinese medicine components and western medicine components.

[0013] In some embodiments of the present application, the soft capsules include, but are not limited to, vitamin and nutritional supplement soft capsules such as propolis soft capsules, fish oil soft capsules, vitamin D3 soft capsules, vitamin C soft capsules, vitamin E soft capsules; traditional Chinese medicine soft capsules such as Huoxiang Zhengqi soft capsules, Guizhifuling capsules, compound Danshen dripping pills, etc.; and western medicine soft capsules such as itraconazole soft capsules, progesterone soft capsules, and loratadine soft capsules, etc.

[0014] Preferably, the raw materials for preparing the capsule material include carrageenan 100-200 parts, galactose 10-40 parts, mannose 40-80 parts, and water 50-400 parts by weight.

[0015] More preferably, the raw materials for preparing the capsule material include carrageenan 120-175 parts, galactose 20-30 parts, mannose 50-70 parts, and water 100-175 parts by weight.

[0016] Further preferably, the raw materials for preparing the capsule material include carrageenan 120 parts, galactose 20 parts, mannose 50 parts, and water 120 parts by weight.

[0017] More preferably, the mass ratio of the galactose and mannose is 1:2-4.

[0018] Further preferably, the mass ratio of the galactose and mannose is 1:2-2.5.

[0019] More preferably, the mass ratio of the galactose and mannose is 1:2.5.

[0020] In a second aspect, the present application also provides a method for preparing the non-oil matrix plant soft capsule as described above, which specifically includes the following steps: (1) Preparation of the matrix liquid: PEG-400 and hydroxypropyl maltodextrin are added to water, and stirred until fully dissolved, to obtain the matrix liquid; (2) Preparation of the capsule material liquid: carrageenan is dissolved in an acidic solution, and subjected to high-temperature hydrolysis to obtain hydrolyzed carrageenan; the hydrolyzed carrageenan, galactose, and mannose are added to water and mixed uniformly, to obtain the capsule material liquid; (3) Filling and drying: the active pharmaceutical ingredients are mixed with the matrix liquid to form the content, and the content and the capsule material liquid are prepared by the rotary rolling method and then transferred into a rotating cage for drying, to obtain the soft capsule.

[0021] Further, the acidic solution is any one of formic acid, acetic acid, citric acid, malic acid, and lactic acid solution.

[0022] Further, the mass concentration of the acidic solution is 5-15%.

[0023] Further, in step (2), the temperature of the high-temperature hydrolysis is 80-100℃, and the time is 1-2h.

[0024] Further, in step (3), the temperature of the drying is 25-35℃, and the humidity is 35-55%.

[0025] Compared with the prior art, the present application has the following beneficial effects: (1) The present application solves the corrosion problem of PEG-400 to carrageenan in the capsule material by matching the matrix with a specific composition and the capsule material with a specific composition, and significantly improves the stability of the capsule material; (2) The present application greatly improves the solubility of carrageenan by hydrolyzing it, and further compounding it with galactose and mannose, greatly shortens the drug disintegration time limit; and when the galactose and mannose are within the verified ratio range, the disintegration time limit is further improved; (3) In addition, based on the excellent stability of the capsule material, the stability of the active ingredients in the content, especially the ingredients prone to oxidative degradation, is further ensured. DETAILED DESCRIPTION

[0026] To make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0027] The hydroxypropyl maltodextrin used in the comparative example of the present application is prepared according to the following method: Take 100 parts of hydroxypropyl starch, add 200 parts of deionized water, add 0.2 parts of concentrated sulfuric acid, stir uniformly, heat to 90℃, stir for 30 minutes, stop heating, and add sodium hydroxide to adjust the pH to 7.0 to terminate the reaction; then hot air dry at 80℃ to a moisture content of 8.5% to obtain hydroxypropyl maltodextrin with a DE value of 5.

[0028] Example 1 A non-oily matrix plant soft capsule, the matrix composition is: PEG-400 100 parts, hydroxypropyl maltodextrin 0.1 part and water 0.1 part; the capsule material composition is: carrageenan 100 parts, galactose 10 parts, mannose 40 parts and water 100 parts.

[0029] The preparation method is as follows: (1) Preparation of the matrix liquid: take PEG-400 and hydroxypropyl maltodextrin and add water, stir until fully dissolved, and obtain; (2) Preparation of the capsule material liquid: carrageenan was dissolved in 10% citric acid aqueous solution, and hydrolyzed at 80°C for 1.5h to obtain hydrolyzed carrageenan; the hydrolyzed carrageenan, galactose and mannose were added into water and mixed uniformly to obtain the capsule material liquid; (3) Filling and drying: vitamin E was mixed with the matrix liquid to form the content, and the content and the capsule material liquid were prepared by the rotary rolling method and then transferred into a rotating cage for drying at 25°C for 20h to obtain the soft capsule.

[0030] Example 2 A non-oil matrix plant soft capsule, wherein the matrix comprises PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 part; and the capsule material comprises carrageenan 120 parts, galactose 20 parts, mannose 50 parts and water 120 parts.

[0031] The preparation method is the same as that in Example 1.

[0032] Example 3 A non-oil matrix plant soft capsule, wherein the matrix comprises PEG-400 100 parts, hydroxypropyl maltodextrin 2 parts and water 1 part; and the capsule material comprises carrageenan 150 parts, galactose 25 parts, mannose 60 parts and water 150 parts.

[0033] The preparation method is the same as that in Example 1.

[0034] Example 4 A non-oil matrix plant soft capsule, wherein the matrix comprises PEG-400 100 parts, hydroxypropyl maltodextrin 5 parts and water 2 parts; and the capsule material comprises carrageenan 175 parts, galactose 30 parts, mannose 70 parts and water 175 parts.

[0035] The preparation method is the same as that in Example 1.

[0036] Example 5 A non-oil matrix plant soft capsule, wherein the matrix comprises PEG-400 100 parts, hydroxypropyl maltodextrin 10 parts and water 5 parts; and the capsule material comprises carrageenan 200 parts, galactose 40 parts, mannose 80 parts and water 200 parts.

[0037] The preparation method is the same as that in Example 1.

[0038] Example 6 A non-oil matrix plant soft capsule, wherein the matrix comprises PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 part; and the capsule material comprises carrageenan 120 parts, galactose 30 parts, mannose 40 parts and water 120 parts.

[0039] The preparation method is the same as that in Example 1.

[0040] Example 7 A non-oily base vegetable soft capsule, the base composition is: PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 parts; the capsule material composition is: carrageenan 120 parts, galactose 10 parts, mannose 60 parts and water 120 parts.

[0041] The preparation method is the same as example 1.

[0042] Example 8 A non-oily base vegetable soft capsule, the base composition is: PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 parts; the capsule material composition is: carrageenan 120 parts, galactose 10 parts, mannose 60 parts and water 120 parts.

[0043] The preparation method is the same as example 1.

[0044] Comparative example 1 A non-oily base vegetable soft capsule, the base composition is: PEG-400 100 parts, hydroxypropyl maltodextrin (DE value is 5) 2 parts, potassium chloride 0.2 parts and water 2 parts; the capsule material composition is: pregelatinized hydroxypropyl starch 120 parts, carrageenan 30 parts, glycerol 40 parts and water 150 parts.

[0045] The preparation method is as follows: (1) Preparation of base liquid: take PEG-400, hydroxypropyl maltodextrin, potassium chloride and add them into water, stir until fully dissolved, and then obtain; (2) Preparation of capsule material liquid: take pregelatinized hydroxypropyl starch, carrageenan and glycerol and add them into water, heat and stir at 90°C until fully dissolved, and then obtain; (3) Filling and drying: mix vitamin E with the base liquid to form the content, and then pass the content and the capsule material liquid through the rotary rolling method to prepare and then transfer into a rotating cage for drying at 25°C for 20h, and then obtain the soft capsule.

[0046] Comparative example 2 A non-oily base vegetable soft capsule, the base composition is: PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 parts; the capsule material composition is: carrageenan 120 parts, galactose 10 parts, mannose 60 parts and water 120 parts.

[0047] The preparation method is as follows: (1) Preparation of base liquid: take PEG-400 and hydroxypropyl maltodextrin and add them into water, stir until fully dissolved, and then obtain; (2) Preparation of capsule material liquid: take carrageenan and dissolve it in 10% citric acid aqueous solution, hydrolyze at 80°C for 1.5h to obtain hydrolyzed carrageenan; add the hydrolyzed carrageenan and galactose into water and mix uniformly, and then obtain; (3) Filling and drying: mixing vitamin E with the base liquid to form the content, and then the content and the capsule material liquid are prepared by the rotary rolling method and transferred into a rotating cage for drying at 25℃ for 20h to obtain the soft capsule.

[0048] Comparative Example 3 A non-oily base plant soft capsule, wherein the base composition comprises PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 parts; and the capsule material composition comprises carrageenan 120 parts, mannose 70 parts and water 120 parts.

[0049] The preparation method is as follows: (1) Preparation of the base liquid: PEG-400 and hydroxypropyl maltodextrin are added to water, and stirred until fully dissolved to obtain the base liquid; (2) Preparation of the capsule material liquid: carrageenan is dissolved in 10% citric acid aqueous solution, and hydrolyzed at 80℃ for 1.5h to obtain hydrolyzed carrageenan; the hydrolyzed carrageenan and mannose are added to water and mixed uniformly to obtain the capsule material liquid; (3) Filling and drying: mixing vitamin E with the base liquid to form the content, and then the content and the capsule material liquid are prepared by the rotary rolling method and transferred into a rotating cage for drying at 25℃ for 20h to obtain the soft capsule.

[0050] Comparative Example 4 A non-oily base plant soft capsule, wherein the base composition comprises PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 parts; and the capsule material composition comprises carrageenan 120 parts, mannose 70 parts and water 120 parts.

[0051] The preparation method is as follows: (1) Preparation of the base liquid: PEG-400 and hydroxypropyl maltodextrin are added to water, and stirred until fully dissolved to obtain the base liquid; (2) Preparation of the capsule material liquid: carrageenan is dissolved in 10% citric acid aqueous solution, and hydrolyzed at 80℃ for 1.5h to obtain hydrolyzed carrageenan; the hydrolyzed carrageenan and mannose are added to water and mixed uniformly to obtain the capsule material liquid; (3) Filling and drying: mixing vitamin E with the base liquid to form the content, and then the content and the capsule material liquid are prepared by the rotary rolling method and transferred into a rotating cage for drying at 25℃ for 20h to obtain the soft capsule.

[0052] Comparative Example 5 A non-oily base plant soft capsule, wherein the base composition comprises PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 parts; and the capsule material composition comprises carrageenan 120 parts, mannose 70 parts and water 120 parts.

[0053] The preparation method is as follows: (1) Preparation of the matrix liquid: PEG-400 and hydroxypropyl maltodextrin were added to water and stirred until fully dissolved, thereby obtaining the matrix liquid; (2) Preparation of the capsule material liquid: carrageenan was dissolved in a 10% citric acid aqueous solution and hydrolyzed at 80°C for 1.5 h to obtain hydrolyzed carrageenan; the hydrolyzed carrageenan, galactose, and arabinose were added to water and mixed uniformly, thereby obtaining the capsule material liquid; (3) Filling and drying: vitamin E was mixed with the matrix liquid to form the content, and the content and the capsule material liquid were prepared by the rotary rolling method and then transferred into a rotating cage for drying at 25°C for 20 h, thereby obtaining the soft capsules.

[0054] Comparative Example 6 A non-oily matrix plant soft capsule, wherein the matrix comprises PEG-400 100 parts, hydroxypropyl maltodextrin 1 part, and water 0.5 parts; and the capsule material comprises carrageenan 120 parts, glucose 20 parts, arabinose 50 parts, and water 120 parts.

[0055] The preparation method is as follows: (1) Preparation of the matrix liquid: PEG-400 and hydroxypropyl maltodextrin were added to water and stirred until fully dissolved, thereby obtaining the matrix liquid; (2) Preparation of the capsule material liquid: carrageenan was dissolved in a 10% citric acid aqueous solution and hydrolyzed at 80°C for 1.5 h to obtain hydrolyzed carrageenan; the hydrolyzed carrageenan, galactose, and arabinose were added to water and mixed uniformly, thereby obtaining the capsule material liquid; (3) Filling and drying: vitamin E was mixed with the matrix liquid to form the content, and the content and the capsule material liquid were prepared by the rotary rolling method and then transferred into a rotating cage for drying at 25°C for 20 h, thereby obtaining the soft capsules.

[0056] Test Example 1: Test of the disintegration and rupture performance of soft capsules The soft capsules prepared in the above examples and comparative examples were placed in a condition of 40±2°C and relative humidity of 75±5% for 6 months, and the disintegration time and rupture time of the soft capsules were tested before starting, at 1 month, and at 6 months, respectively, according to the following test method: (1) Disintegration time: the disintegration time was tested according to the disintegration time limit test method in the Chinese Pharmacopoeia 2020 edition, water was used as the medium (temperature was 37°C), each group of soft capsules was tested in parallel for 6 times, and the average value was taken as the disintegration time. The results are shown in Table 1.

[0057] (2) Rupture time: the paddle method was used for the test according to the US Pharmacopoeia 32 edition, the rotation speed was 50 r / min, the medium was water 500 ml, and the temperature was 37°C. The soft capsules were put into the dissolution cup, and after the capsule sank to the bottom of the cup, the paddle was started, and the time of rupture of each capsule shell was observed and recorded. Each group of soft capsules was tested in parallel for 6 times, and the average value was taken as the rupture time. The results are shown in Table 2.

[0058]

[0059]

[0060] From the above results, it can be seen that the initial disintegration time of the soft capsules prepared in Examples 1-8 is within 6 minutes, the initial rupture time is within 4 minutes, and the soft capsules have excellent disintegration and rupture performance. Meanwhile, the stability of the soft capsules is good under accelerated conditions for 6 months, the disintegration time increases by less than 15%, and the rupture time increases by less than 10%. Among them, Examples 2-4 are more optimal, the initial disintegration time is within 5 minutes, and the disintegration time increases by less than 8% under accelerated conditions for 6 months.

[0061] Compared with Example 2, the initial disintegration time and rupture time of Example 8 are longer, but the stability is also better; although the disintegration time and rupture time of Comparative Examples 4 and 5 also reach the level of Example 8, the stability is poor, and the disintegration time and rupture time are both prolonged by more than 20%; it can be seen that there is a big difference in the allocation ratio of each component, which slightly affects the initial disintegration and rupture performance, but can improve the stability, and galactose and mannose in the capsule material are the key to improving the stability of the soft capsule. In addition, in Comparative Examples 2 and 3, not only the stability is poor, but also the initial disintegration and rupture time is longer, which shows that galactose and mannose have a significant synergistic effect on improving the disintegration and rupture performance and stability of the soft capsule material.

[0062] Test Example 2: Stability test of soft capsules The soft capsules prepared in the above examples and comparative examples are placed under the conditions of a temperature of 40±2℃ and a relative humidity of 75±5% for 6 months, and the shape is observed and the peroxide value is measured at 0, 3, and 6 months.

[0063]

[0064] From the above table, it can be seen that the stability of vitamin E in the vitamin E soft capsules prepared in Examples 1-8 and Comparative Example 1 is higher; and the change of the capsule material in Comparative Examples 2-6 leads to a decrease in the stability of vitamin E to varying degrees. It can be seen from Comparative Examples 2 and 3 compared with Example 2 that galactose and mannose as raw materials of the capsule material show a synergistic effect on improving the stability of vitamin E, but after replacing either one or both of them with other components having similar functions, the stability cannot reach the effect of the combination of the two.

[0065] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A non-oily base vegetable soft capsule characterized in that, It is composed of a capsule material and a content; the content is composed of a pharmaceutical active ingredient and a matrix; the matrix is prepared from PEG-400, hydroxypropyl maltodextrin and water; and the capsule material is prepared from carrageenan, galactose, mannose and water.

2. The non-oily base soft vegetable capsule according to claim 1, characterized in that, The matrix is prepared from PEG-400 100 parts, hydroxypropyl maltodextrin 0.1-20 parts and water 0.1-5 parts by weight; And / or the capsule material is prepared from carrageenan 100-200 parts, galactose 10-40 parts, mannose 40-80 parts and water 50-400 parts by weight.

3. The non-oily base soft vegetable capsule according to claim 2, characterized in that, The matrix is prepared from PEG-400 100 parts, hydroxypropyl maltodextrin 1-10 parts and water 0.5-2 parts by weight; And / or the capsule material is prepared from carrageenan 120-175 parts, galactose 20-30 parts, mannose 50-70 parts and water 100-175 parts by weight.

4. The non-oily base soft vegetable capsule according to claim 3, characterized in that, The matrix is prepared from PEG-400 100 parts, hydroxypropyl maltodextrin 1 part and water 0.5 parts by weight; And / or the capsule material is prepared from carrageenan 120 parts, galactose 20 parts, mannose 50 parts and water 120 parts by weight.

5. The non-oily base soft vegetable capsule according to claim 1, wherein The mass ratio of galactose to mannose is 1:2-4.

6. The non-oily base soft vegetable capsule according to claim 5, characterized in that, The mass ratio of galactose to mannose is 1:2-2.

5.

7. The non-oily base soft vegetable capsule according to any one of claims 1 to 6, characterized in that, The water content of the carrageenan is 7.5-12.5%.

8. The method of preparing a non-oily base softgel of a plant of any one of claims 1-7, wherein, It comprises the following steps: (1) Preparation of the matrix liquid: PEG-400 and hydroxypropyl maltodextrin are added to water and stirred until fully dissolved, and then the matrix liquid is obtained; (2) Preparation of the capsule material liquid: carrageenan is dissolved in an acidic solution, and then hydrolyzed at high temperature to obtain hydrolyzed carrageenan; the hydrolyzed carrageenan, galactose and mannose are added to water and mixed uniformly, and then the capsule material liquid is obtained; (3) Filling and drying: the pharmaceutical active ingredient is mixed with the matrix liquid to form the content, and then the content and the capsule material liquid are prepared by the rotary rolling method and transferred into a rotating cage for drying, and then the soft capsules are obtained.

9. The production method according to claim 8, characterized by, The acidic solution is one or more of formic acid, acetic acid, citric acid, malic acid and lactic acid solution.

10. The preparation method according to claim 8, characterized in that, In step (2), the high-temperature hydrolysis is carried out at a temperature of 80-100℃ for 1-2h; And / or in step (3), the drying is carried out at a temperature of 25-35℃ and a humidity of 35-55%.

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