A kind of hypromellose film-forming composition and its application

Abstract

The present invention belongs to the field of medicine and dietary supplement manufacturing, and specifically relates to a hydroxypropyl methylcellulose film-forming composition and its application. By weight, the raw materials of the hydroxypropyl methylcellulose film-forming composition include: 80-120 parts of hydroxypropyl methylcellulose, 0.25-5 parts of the first gellan gum and 0.25-3 parts of the second gellan gum; each repeating unit of the first gellan gum contains 1%-30% of acetyl and 15%-40% of glyceryl acyl, and each repeating unit of the second gellan gum contains 20%-45% of acetyl and 30%-55% of glyceryl acyl. The present invention determines the acyl content of gellan gum suitable for delayed release hollow capsules, and combines two gellan gums with different acyl contents. The combination can make the amount of gellan gum added lower, and the capsule molding effect is better and the production conditions are milder after adding a coagulant.

Description

Technical Field

[0001] The invention belongs to the field of medicine and dietary supplement manufacturing, and specifically relates to a hydroxypropyl methylcellulose film-forming composition and application thereof. Background Art

[0002] Certain drugs require rapid release of their efficacy in the intestines, and the drugs need to pass through the stomach first and then the intestines. If the drugs are not specially treated, they are easily dissolved and released in the stomach and cannot exert their efficacy in the intestines, resulting in reduced efficacy. In order to improve the adaptability of taking, it is usually chosen to fill the drugs into capsule shells.

[0003] At present, three methods are used to achieve the purpose of making the drug insoluble in the stomach but dissolving rapidly in the intestine: ① Wrap the drug with a layer of enteric coating and fill it into an ordinary capsule shell; ② After the drug is filled into the capsule shell, wrap the capsule shell with a layer of enteric coating; ③ Use the secondary dipping method to produce an enteric capsule shell, and then fill the drug into the capsule. The above three methods all involve enteric materials. Most of the enteric materials are polymers containing carboxyl groups. They are characterized by being insoluble in water under gastric acid conditions (pH 1.2) and easily soluble in water under intestinal conditions (pH 6.8). Common enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), etc. The solution formed after these substances are dissolved under specific conditions can be used as a coating solution, and an enteric coating is formed after drying. However, the main disadvantages of the coating method are complex production process, high production cost, high professionalism, and easy residue of toxic organic solvents. The secondary dipping method in the third method has higher requirements on capsule production equipment and also has the above-mentioned problems.

[0004] Chinese invention patent application CN 102665697 A discloses an acid-resistant capsule formed by one-time dipping. The acid-resistant capsule in the invention is prepared by gellan gum, HPMC and water without adding a coagulant, wherein the weight ratio of HPMC to gellan gum is 100:(4-15), and the preferred weight ratio is 100:(4.5-6). The acid-resistant capsule prepared by the water-soluble composition does not leak in a pH 1.2 medium within 1 hour, and the filler is rapidly released in a pH 6.8 medium. The invention has the following conclusions through research: (1) A lower content of gellan gum cannot make the capsule show excellent acid resistance in a pH 1.2 medium. When the gellan gum content is 2% and 3%, the dissolution time is 21 minutes and 24 minutes respectively. When the gellan gum content reaches 4.5% and above, it can achieve no leakage within 1 hour; (2) The reason why the capsule can be formed without adding a coagulant is that gellan gum naturally contains a certain amount of coagulant (such as cations), which helps the gellan gum gel, so there is no need to add a coagulant. However, the invention does not specify the type of gellan gum, and the properties of different types of gellan gum are very different. Therefore, when the amount of gellan gum added is less than 4%, there is also the possibility that the capsule is resistant to acid. In addition, according to capsule production experience, when large-scale production is carried out, capsules without adding coagulant aids may have problems such as uneven product wall thickness and thin top during the production process.

[0005] Capsules containing gellan gum have certain acid resistance, but when gellan gum from different manufacturers is added, the acid resistance varies greatly. Therefore, it is considered that the properties of gellan gum itself directly affect the acid resistance of the capsule. Gellan gum, also known as kelp gum, is a high molecular linear polysaccharide composed of repeated polymerization of basic units consisting of 4 monosaccharide molecules. Its basic unit is composed of 2 glucose residues connected by 1,3- and 1,4-linked, 1 glucuronic acid residue connected by 1,3-, and 1 rhamnose residue connected by 1,4-. Natural gellan gum contains O-acyl groups (glycerol acyl and acetyl groups). Natural or high acyl gellan gum can form a high elasticity and low hardness gel. Acetylated gellan gum is treated with alkali to remove the O-acyl group to generate low acyl gellan gum. The structures of low acyl and high acyl gellan gum are as follows:

[0006] .

[0007] Therefore, in the research of this field, there is still a need to study a delayed-release capsule that can be formed by one-time dipping, while ensuring good formability, avoiding the use of toxic organic solvents, so as to achieve the purpose of making the capsule insoluble in the stomach and dissolving in the intestine. Summary of the invention

[0008] The inventors found in the long-term capsule production research process that the capsules containing gellan gum have certain acid resistance, but when gellan gum from different manufacturers is added, the acid resistance varies greatly. Therefore, it is considered that the properties of gellan gum itself directly affect the acid resistance of the capsule.

[0009] Gellan gum is divided into high acyl and low acyl gellan gum. The main difference between high acyl gellan gum and low acyl gellan gum in structure is that each repeating unit of high acyl gellan gum has an acyl group connected to the glucose molecule, and its acyl group is divided into two categories: one is an acetyl group connected to the 6th carbon atom of the glucose molecule by a β-1,3 bond; the other is a glyceryl group connected to the 2nd carbon atom of the glucose molecule by a β-1,3 bond, wherein the average proportion of the glyceryl group is twice that of the acetyl group. It is precisely because of the presence of acetyl and glyceryl groups in the molecule that high acyl gellan gum exhibits different properties from low acyl gellan gum. By subjecting high acyl gellan gum to high temperature and alkali treatment, part of the acetyl and glyceryl acyl groups in its structure can be removed, thereby controlling the acyl content on the gellan gum to obtain deacylated gellan gum. The inventors have investigated deacylated gellan gum with different acyl contents and found the optimal gellan gum compounding ratio, which can be applied to the production of delayed release capsules, and the product has excellent acid resistance.

[0010] In order to achieve the above object, the present invention adopts the following technical solutions:

[0011] On the one hand, a hydroxypropyl methylcellulose film-forming composition is provided, wherein the raw materials of the hydroxypropyl methylcellulose film-forming composition include, by weight: 80-120 parts of hydroxypropyl methylcellulose, 0.25-5 parts of a first gellan gum, and 0.25-3 parts of a second gellan gum; preferably, 100 parts of hydroxypropyl methylcellulose, 1.5-2.5 parts of the first gellan gum, and 0.75-1.5 parts of the second gellan gum; further preferably, 100 parts of hydroxypropyl methylcellulose, 2-2.5 parts of the first gellan gum, and 1-1.5 parts of the second gellan gum;

[0012] Each repeating unit of the first gellan gum contains 1%-30% of acetyl and 15%-40% of glyceryl, and each repeating unit of the second gellan gum contains 20%-45% of acetyl and 30%-55% of glyceryl.

[0013] Preferably, each repeating unit of the first gellan gum contains 18%-30% of acetyl groups and 20%-40% of glyceryl groups, and each repeating unit of the second gellan gum contains 25%-35% of acetyl groups and 40%-50% of glyceryl groups.

[0014] Preferably, the types of the first gellan gum and the second gellan gum are selected from any one of TW-J100, TW-J300, TW-J500 and TW-HGX.

[0015] Further preferably, the model of the first gellan gum is TW-J100, and the model of the second gellan gum is TW-J500.

[0016] Preferably, the weight ratio of the first gellan gum to the second gellan gum is 1:5-5:1.

[0017] Further preferably, the weight ratio of the first gellan gum to the second gellan gum is 2:1.5-2.5:1.

[0018] Preferably, the raw materials of the hydroxypropyl methylcellulose film-forming composition further include, by weight: 0.2-0.8 parts of a coagulant and 300-600 parts of water, wherein the coagulant is selected from one or more of potassium chloride, sodium chloride, potassium acetate, potassium citrate, potassium bicarbonate, sodium bicarbonate and sodium carbonate, preferably sodium chloride.

[0019] Preferably, the type of hypromellose is selected from one or both of type 2910 and type 2906.

[0020] On the other hand, a method for preparing a hard capsule shell from the hydroxypropyl methylcellulose film-forming composition of the present invention is provided, comprising the steps of sol, dip, drying, capsule extraction, length setting, cutting and sleeve fitting, wherein the sol step comprises: heating water, adding hydroxypropyl methylcellulose, a first gellan gum, a second gellan gum and / or a coagulant, mixing, homogenizing, removing bubbles, and standing to obtain a glue solution.

[0021] Preferably, the water is heated to 60-90° C., the homogenization time is 1-2 h, and the standing time is 0-6 h.

[0022] Preferably, the dipping in glue comprises: immersing the capsule mold needle in glue solution, and dipping in glue for 0.5-1.5s.

[0023] Preferably, the drying temperature is 18-38°C, and the drying time is 1-4h; specifically, after drying through 8 air ducts, the temperature of air duct 1 is set to 18-23°C, the temperature of air duct 2 is set to 20-30°C, the temperature of air duct 3 is set to 25-38°C, the temperature of air ducts 4-8 is set to 25-35°C, and the drying time of each air duct 1-8 is 10-30min.

[0024] In another aspect, a delayed-release hollow capsule shell is provided, which is prepared by the method of the present invention.

[0025] Compared with the prior art, the present invention has the following technical advantages and beneficial effects:

[0026] (1) The inventors conducted research on the acyl content of gellan gum and determined the acyl content of gellan gum suitable for delayed-release hollow capsules. They combined two gellan gums with different acyl contents. This combination can reduce the amount of gellan gum added, and after adding a coagulant, the capsule molding effect is better and the production conditions are milder.

[0027] (2) The present invention provides a composition for producing delayed-release capsules, which does not contain toxic organic solvents, thus avoiding solvent residues and reducing the risk of taking the capsules.

[0028] (3) The present invention provides a production process for delayed-release capsules. No secondary dipping is required in the process flow, which reduces the difficulty of production technology. The process parameters and actual operation are conducive to large-scale production and do not require professional personnel to operate.

[0029] (4) The capsule of the present invention has a good molding effect. By adding a coagulant, the capsule is easier to mold, and the top thickness and wall thickness are easier to control. There will be no defects such as thin top and uneven wall thickness.

[0030] (5) The delayed-release hollow capsule of the present invention has no obvious leakage in a pH 1.2 simulated gastric fluid medium within 1 hour, and releases rapidly in a pH 6.8 simulated intestinal fluid medium, thereby proving its delayed-release function. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is a comparison chart of the dissolution curves of the capsule in Example 8 and ordinary commercially available capsules. DETAILED DESCRIPTION

[0032] The present invention will be further described in detail below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only intended to illustrate the present invention. The experimental methods used in the following examples are generally conventional, unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available, unless otherwise specified.

[0033] The acyl content of gellan gum is shown in Table 1. Gellan gum No. ①-⑥ was purchased from Zhejiang Tianwei Biotechnology Co., Ltd.

[0034] Table 1 Gellan gum serial number and acyl content

[0035]

[0036] Examples 1-6

[0037] The raw materials and addition amounts of the hydroxypropyl methylcellulose film-forming compositions of Examples 1-6 are shown in Table 2.

[0038] The preparation steps of the delayed release hollow capsule shell are as follows:

[0039] (1) Sol: After the water is heated to 72°C, add hydroxypropyl methylcellulose, the first gellan gum, the second gellan gum and the coagulant, mix well, put into the sol kettle, stir, and homogenize for 1.5 hours to obtain a uniform gel solution;

[0040] (2) Dipping in glue: Dip the No. 0 capsule mold needle into the glue solution. After dipping in glue for 1 second, turn it over and raise it. The insulation temperature of the glue tank is 68°C.

[0041] (3) Drying: The temperature of air duct 1 is set to 20°C, the temperature of air duct 2 is set to 24°C, the temperature of air duct 3 is set to 35°C, and the temperature of air ducts 4-8 is set to 30°C;

[0042] (4) Extracting the capsule: extracting the dried capsule;

[0043] (5) Fixed length, cutting, and fitting: Cut the capsule to a fixed length and fit the body and cap together;

[0044] (6) Filling: A capsule filling machine is used for filling, and each capsule is filled with the same weight of acetaminophen powder.

[0045] Examples 1-3 all used pilot equipment and the method in USP-35 to measure the dissolution performance of the test samples in a medium simulating gastric fluid (pH 1.2), and the test results are shown in Table 2. The test samples were consistent with conventional product sizes and specifications.

[0046] Table 2: Feeding amount and dissolution of compositions of Examples 1-6

[0047]

[0048] Comparative Examples 1-10

[0049] The formulations, dosages and dissolution conditions of the compositions of Comparative Examples 1-10 are shown in Table 3. The preparation methods and testing methods of the delayed-release hollow capsule shells are consistent with those of Examples 1-6.

[0050] Table 3 Comparative Examples 1-6 Composition Feeding Amount and Dissolution

[0051]

[0052] Embodiment 7-9

[0053] Examples 7-9 were all prepared using large-scale production equipment and the same method to prepare 4 million 00# capsules. The dissolution performance of the test samples was determined in a medium simulating gastric fluid (pH 1.2) and a medium simulating intestinal fluid (pH 6.8) using the method in the Japanese Pharmacopoeia. Table 4 shows the composition dosage, capsule forming, and dissolution of Examples 7-9. The test samples are industrial products and have more reference significance for actual production.

[0054] The preparation steps of the delayed release hollow capsule shell are as follows:

[0055] (1) Sol: Heat water to 72°C, add hydroxypropyl methylcellulose, first gellan gum, second gellan gum and coagulant, mix well, put into a sol kettle, stir, homogenize for 2 hours, vacuum to remove bubbles, let stand for 1 hour, and obtain a uniform gel solution;

[0056] (2) Dipping in glue: Dip the No. 0 capsule mold needle into the glue solution. After dipping in glue for 1 second, turn it over and raise it. The insulation temperature of the glue tank is 68°C.

[0057] (3) Drying: The temperature of air duct 1 is set to 22°C, the temperature of air duct 2 is set to 25°C, the temperature of air duct 3 is set to 38°C, and the temperature of air ducts 4-8 is set to 28°C. The drying time of air duct 1 is 4 minutes, the drying time of air duct 2 is 18 minutes, the drying time of air duct 3 is 25 minutes, and the drying time of each air duct 4-8 is 20 minutes;

[0058] (4) Extracting the capsule: extracting the dried capsule;

[0059] (5) Fixed length, cutting, and fitting: Cut the capsule to a fixed length and fit the body and cap together;

[0060] (6) Filling: A capsule filling machine is used for filling, and each capsule is filled with the same weight of acetaminophen powder.

[0061] Table 4: Composition dosage, capsule forming and dissolution of Examples 7-9

[0062]

[0063] Comparative Example 11

[0064] The composition formula and feed amount of Comparative Example 11, as well as the capsule forming and dissolution conditions are shown in Table 5. The preparation method and testing method of the delayed-release hollow capsule shell are consistent with those of Examples 7-9.

[0065] Table 5 Comparative Example 11 Composition formula and dosage and capsule forming and dissolution

[0066]

[0067] Table 6 is a comparison of the capsule quality test data of Examples 7-9 and Comparative Example 11.

[0068] Table 6 Capsule quality test data

[0069]

[0070] Note: / indicates no such defect, √ indicates the existence of such defect.

[0071] In the process of batch production, the capsules obtained by the method of the present invention in Examples 7-9 have good molding effect, high qualified rate, can be stably batch produced, and have acid resistance. However, in the actual production process, the capsules of Comparative Example 11 are prone to gel flow, and have problems such as thin top, uneven wall thickness, and thick mouth, which are problematic in practical applications.

[0072] Figure 1 The dissolution curves of the capsules of Example 8 and common commercially available capsules show that the delayed-release capsules prepared by the method of the present invention have good acid resistance and can be rapidly released in simulated intestinal fluid, achieving the delayed-release effect.

[0073] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A hydroxypropyl methylcellulose film-forming composition for delayed-release hollow capsule shells, characterized in that: The raw materials of the hydroxypropyl methylcellulose film-forming composition include, by weight: 80-120 parts of hydroxypropyl methylcellulose, 0.25-1.5 parts of a first gellan gum, 0.25-1.5 parts of a second gellan gum, 0.2-0.8 parts of a coagulant aid, and 300-600 parts of water; Each repeating unit of the first gellan gum contains 18%-23% of acetyl groups and 20%-31% of glyceryl groups, and each repeating unit of the second gellan gum contains 25%-35% of acetyl groups and 40%-50% of glyceryl groups; The weight ratio of the first gellan gum to the second gellan gum is 1:1-5:

1.

2. The hypromellose film-forming composition according to claim 1, characterized in that The first gellan gum is selected from TW-J100 or TW-J300; the model of the second gellan gum is selected from TW-J500.

3. The hypromellose film-forming composition according to claim 2, characterized in that The model of the first gellan gum is TW-J100, and the model of the second gellan gum is TW-J500.

4. The hypromellose film-forming composition according to claim 1, characterized in that The weight ratio of the first gellan gum to the second gellan gum is 2:1.5-2.5:

1.

5. The hypromellose film-forming composition according to claim 1, characterized in that The coagulant aid is selected from one or more of potassium chloride, sodium chloride, potassium acetate, potassium citrate, potassium bicarbonate, sodium bicarbonate and sodium carbonate; the type of hydroxypropyl methylcellulose is selected from one or both of type 2910 and type 2906.

6. A method for preparing a delayed-release empty capsule shell from the hypromellose film-forming composition according to any one of claims 1 to 5, characterized in that: The method comprises the steps of sol, dip, dry, extract, length, cut and sheath, wherein the sol step comprises: heating water, adding hydroxypropyl methylcellulose, first gellan gum, second gellan gum and coagulant, mixing, homogenizing, removing bubbles and standing to obtain glue solution.

7. The method according to claim 6, characterized in that The water is heated to 60-90° C., the homogenization time is 1-2 hours, and the standing time is 0-6 hours; the dipping in glue includes: immersing the capsule mold needle in the glue solution and dipping in glue for 0.5-1.5 seconds; the drying temperature is 18-38° C., and the drying time is 1-4 hours.

8. A delayed-release hollow capsule shell prepared by the method according to any one of claims 6 to 7.

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