Pullulan capsules

Abstract

The present invention discloses a hard capsule shell comprising pullulan, low acyl gellan, high acyl gellan, and KCl.

Description

Technical Field

[0001] The present invention discloses a hard capsule shell containing pullulan, low-acyl gellan, high-acyl gellan, and KCl.

Background Art

[0002] Hard capsules are used as a dosage form for pharmaceuticals or dietary supplements.

[0003] US3,258,115 discloses a two-piece hard gelatin capsule, and gelatin forms the shell of the capsule. [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0009] CAPSSHELL is a two-piece rigid capsule shell. The two pieces are the cap and body of the capsule shell, which are joined together in an expandable and contractible manner when CAPSSHELL is closed.

[0010] Preferably, CAPSSHELL does not contain gelatin, HPMC, PVA, or modified starch.

[0011] Preferably, CAPSSHELL does not contain a polymer selected from the group consisting of HPMCAS, HPMCP, CAP, and polyacrylic acid copolymers.

[0012] More preferably, CAPSSHELL does not contain any other film-forming polymers other than pullulan.

[0013] Low-acylgelanes, high-acylgelanes, and combinations thereof are known to those skilled in the art as gelling agents.

[0014] It is known to those skilled in the art that KCl acts as a gelling aid when used in combination with a gelling agent. Therefore, the combination of low-acylgelane, high-acylgelane, and KCl in CAPSSHELL is a combination of gelling agent and gelling aid.

[0015] Preferably, CAPSSHELL does not contain any gelling agents other than combinations of low-acylgerane and high-acylgerane, and CAPSSHELL does not contain any combination of gelling agents and gelling aids other than the combination of low-acylgerane, high-acylgerane, and KCl.

[0016] Preferably, CAPSSHELL is 95-98.4% by weight of pullulan, Low acylgeran of 0.25-0.45% by weight, 0.15~0.45% by weight of high acyl gelane, It contains 1.2 to 1.8% by weight of KCl, The weight percentages are based on the dry capsule weight.

[0017] More preferably, CAPSSHELL is 95 to 98.3% by weight of pullulan, 0.3 to 0.4% by weight of low acyl gellan, 0.2 to 0.4% by weight of high acyl gellan, containing 1.2 to 1.6% by weight of KCl, The weight percentages are based on the dry capsule weight.

[0018] In one embodiment, CAPSSHELL further contains sucrose monolaurate.

[0019] Preferably, when CAPSSHELL contains sucrose monolaurate, CAPSSHELL contains 0.05 to 0.25% by weight, more preferably 0.1 to 0.2% by weight of sucrose monolaurate, and the weight percentages are based on the dry capsule weight.

[0020] In one embodiment, CAPSSHELL further contains sorbitan monolaurate.

[0021] Preferably, when CAPSSHELL contains sorbitan monolaurate, CAPSSHELL contains 0.01 to 0.05% by weight, more preferably 0.02 to 0.04% by weight of sorbitan monolaurate, and the weight percentages are based on the dry capsule weight.

[0022] In one embodiment, CAPSSHELL further contains NaHCO3.

[0023] Preferably, when CAPSSHELL contains NaHCO3, CAPSSHELL contains 0.02 to 0.06% by weight, more preferably 0.03 to 0.05% by weight of NaHCO3, and the weight percentages are based on the dry capsule weight.

[0024] CAPSSHELL may contain water. Since water may arise from production processes that may use aqueous compositions to prepare CAPSSHELL, the water in CAPSSHELL is typically residual water remaining in CAPSSHELL after drying.

[0025] Furthermore, water may originate from the humidity of the atmosphere surrounding the CAPSSHELL, essentially the relative humidity of the air. A typical upper limit for the amount of residual water in the CAPSSHELL is 20% by weight or less, preferably 15% by weight or less, and more preferably 10% by weight or less, where the weight percentage is based on the weight of the CAPSSHELL.

[0026] The typical lower limit of the amount of residual water in CAPSSHELL is 1% by weight or more, preferably 2% by weight or more, and more preferably 3% by weight or more, where the weight percentage is based on the weight of CAPSSHELL.

[0027] Any of the lower limits for the amount of residual water can be combined with any of the upper limits for the amount of residual water.

[0028] For example, the amount of residual water in CAPSSHELL may be 1 to 20% by weight, preferably 2 to 15% by weight, and more preferably 3 to 10% by weight, where the weight percentage is based on the weight of CAPSSHELL.

[0029] The amount of residual water can be characterized by the loss on drying (LOD). The dry capsule weight is the capsule weight minus the weight lost when the LOD is determined, i.e., the weight of the capsule remaining after the LOD determination.

[0030] In one embodiment, CAPSSHELL consists of pullulan, low acylgerane, high acylgerane, KCl, sucrose monolaurate, sorbitan monolaurate, NaHCO3, and water. Preferably, CAPSSHELL contains at least 95% by weight of pullulan, where the weight percentage is based on the weight of CAPSSHELL.

[0031] A further subject of the present invention is a method for preparing CAPSSHEL, CAPSSHELL is prepared by dip molding. CAPSSHELL is as defined herein, including all embodiments thereof.

[0032] When CAPSSHELL uses an aqueous mixture of its components for dip molding, this aqueous mixture is referred to as the melt.

[0033] Molding pins are dipped in the melt and then extracted from the molten material. The melt on the outer surface of the molding pins solidifies to form a film, which is still a wet gel. The film is then dried at 20-80°C. After drying, the unwanted parts are cut off to produce the body and cap, respectively. Molding pins of each shape are used for dip molding to produce the body, and molding pins of each shape are used for dip molding to produce the cap. The body and cap pairs constitute a CAPSSHELL, and a closed CAPSSHELL is obtained by joining the cap to the body in an expandable and contractible manner.

[0034] A further subject of the present invention is a CAPSSHELL filled with an activator AA, where AA is selected from drugs, pharmaceuticals, medicines, therapeutic agents, nutritional supplements, and active pharmaceutical ingredients (APIs). CAPSSHELL is as defined herein, including all embodiments thereof. [Examples]

[0035] Definitions, materials, abbreviations, and methods used herein [Table 2]

[0036] Tube Tester Capsugel, now Lonza Ltd, developed in-house by Visp, Switzerland:

[0037] method: The capsule's fracture and elastic behavior are measured by its resistance to impact tests using the tube.

[0038] procedure: 1. After storing the capsules for 5 days, test them in a desiccator. Available storage conditions are 10%, 23%, 33%, and 45% RH. Store 50 capsules for each condition in an open box. Then, close the box to prevent any moisture exchange with the surrounding atmosphere. 2. Place the capsule horizontally on a flat surface. Place a 3,100g weight into the tube. 4. Place the tube on top of the capsule and press the latch to release the weight. Test 5.50 capsules. After equilibrating with the selected RH, use a sealed storage box and do not remove 50 capsules at a time (to avoid any reabsorption of humidity). Record the number of damaged parts, caps, or capsules (both body and cap).

[0039] Preparation of culture medium pH 1.2 USP: Dissolve 2g of sodium chloride in 700ml of desalinated water. Add 7 ml of concentrated hydrochloric acid (Merck, 37% in water) while stirring. Complete the process with desalinated water up to 1000ml. DM Water USP: Elix® 20 Water Purification System, Millipore, Merck KGaA, Darmstadt, Germany pH 6.8 USP: Solution A: KH2PO40.2M Dissolve 27.22g of potassium dihydrogen phosphate (KH2PO4) in 1000ml of desalted water. Solution B: NaOH 0.2M Dissolve 8.0g of sodium hydroxide (NaOH) in 1000ml of desalted water. pH 6.8 USP: Mix 250 ml of solution A and 112 ml of solution B. The process is completed using desalinated water up to 1000ml.

[0040] Example 1: Preparation of Plantcaps gellan melt [Table 3]

[0041] Step 1 involved preparing the gelan melt by filling a container with deionized water at 80-85°C, which had been filled with NaHCO3 and mixed for 5 minutes. The gelan blend (LAG and HAG) was then added and mixed for 200 minutes.

[0042] The 10% KCl solution prepared according to Step 2 was added to the container and then cooled to 68°C.

[0043] Next, pullulan was added, and the mixture was mixed for 60 minutes. Step 4 in Table 1 shows a summary.

[0044] The mixture was maintained at 68°C for 60 minutes for degassing until no more bubbles were observed, and then for a further 90 minutes for aging to obtain pullulan melt.

[0045] The pullulan melt was transferred to a transfer tank at 65°C.

[0046] A surfactant solution was obtained by mixing 1.4 kg of SE solution prepared according to step 3a and 0.3 kg of SML solution prepared according to step 3b.

[0047] The surfactant solution was gently mixed and added to the pullulan melt in the transfer tank while maintaining a temperature of 65°C to obtain Plantcaps gellan melt for further use in dip molding.

[0048] Table 1 shows the amounts of the components used. Table 2 shows the composition of Plantcaps gellan melt and the composition of the final capsule based on the dry weight of the capsule. [Table 4]

[0049] Example 2: Preparation of Plantcaps gelatin capsules (PGCs) Using Plantcaps gellan melt prepared according to Example 1, shells in the form of capsule halves (body and cap) with capsule size 2 and a standard target weight (capsule weight 61+ / -4mg) were produced by conventional dip molding, which involved dipping stainless steel forming pins at a temperature of 22°C into Plantcaps gellan melt at a temperature of 60°C. A film was formed on the forming pins. After a first drying of the film on the forming pins at 26°C and 44% RH for 15-20 minutes, a second drying was applied at 32°C and 25-30% RH for 30 minutes, and finally, drying at 22°C and 50% RH, after which the capsule components were peeled off the metal pins.

[0050] The capsule halves were removed from the molded pin.

[0051] The capsules were always assembled by joining one cap to one body.

[0052] Example 3: Capsule Testing - Mechanical Performance The fracture behavior of capsules prepared according to Example 2 was measured by their resistance to impact tests using a tube testing machine. For test preparation, capsules were stored in a desiccator under four different storage conditions: 10, 23, 33, and 45% RH for 5 days to equilibrate, in order to obtain capsules with different LODs. Fifty capsules were tested at each RH value, and the number of broken bodies or caps was recorded. The percentage of broken capsules is shown in Table 3.

[0053] capsule: Plantcaps gellan capsules prepared according to PGC Example 2 [Table 5]

[0054] The mechanical properties of PGC and PC are similar, and the deviation is within the normal range of variation in tube testing.

[0055] Example 4: Capsule Test - Capsule Disintegration The capsules prepared according to Example 2 were tested for disintegration using a disintegration tester (Sotax DT2 (SOTAX AG, 4147 Aesch, Switzerland)) in accordance with USP specifications.

[0056] In this study, capsules were filled with 320+ / -10mg of a lactose blend containing 0.1% by weight of indigo carmine pigment.

[0057] The capsules were placed in different culture media at 37°C + / -1°C, and the time of initial leakage, the time it took for the capsule to empty, and the time it took for the capsule to completely disintegrate were recorded.

[0058] Six capsules were tested per culture medium, and the average time for each was calculated.

[0059] The results are shown in Table 4.

[0060] capsule: Plantcaps gellan capsules prepared according to PGC Example 2 [Table 6]

[0061] Example 5: Test with capsules - capsule dissolution Capsules prepared according to Example 2 were tested for solubility in different media: pH 1.2 USP, DM water USP, and pH 6.8 USP, using a Sotax AT70smart (SOTAX AG, 4147 Aesch, Switzerland), a dissolution vessel with a 50 rpm paddle at 37°C. The dissolution of acetaminophen was continued using a Perkin Elmer Lambda 25UV / VIS spectrometer at a wavelength of 300 nm. The capsules were filled with acetaminophen (APAP, Sigma Aldrich Ref A5000).

[0062] Table 5 shows the results as the measured percentage of APAP dissolved in the capsule over time.

[0063] Abbreviations in Table 5: [Table 7] [Table 8]

Claims

1. A rigid capsule shell, 95-98.7% by weight of pullulan, Low acylgerane of 0.2-0.5% by weight, 0.1-0.5% by weight of high acylgerane, Contains 1-2% by weight of KCl, The aforementioned weight percentage is based on the dry capsule weight, CAPSSHELL.

2. The CAPSSHELL according to claim 1, wherein the CAPSSHELL does not contain gelatin, HPMC, PVA, or modified starch.

3. The CAPSSHELL according to claim 1 or 2, wherein the CAPSSHELL does not contain a polymer selected from the group consisting of HPMCAS, HPMCP, CAP, and polyacrylic acid copolymer.

4. The CAPSSHELL according to any one of claims 1 to 3, wherein the CAPSSHELL does not contain any other film-forming polymers other than pullulan.

5. The CAPSSHELL according to any one of claims 1 to 4, wherein the CAPSSHELL does not contain any gelling agents other than a combination of low-acylgerane and high-acylgerane, and the CAPSSHELL does not contain any combination of gelling agent and gelling aid other than a combination of low-acylgerane, high-acylgerane, and KCl.

6. The aforementioned CAPSSHELL, 95-98.4% by weight of pullulan, Low acylgerane of 0.25-0.45% by weight, 0.15-0.45% by weight of high acylgerane, It contains 1.2 to 1.8% by weight of KCl, The CAPSSHELL according to any one of claims 1 to 5, wherein the aforementioned weight % is based on the dry capsule weight.

7. The aforementioned CAPSSHELL, 95-98.3% by weight of pullulan, 0.3-0.4% by weight of low acylgerane, 0.2-0.4% by weight of high acylgerane, It contains 1.2 to 1.6% by weight of KCl, The CAPSSHELL according to any one of claims 1 to 6, wherein the aforementioned weight % is based on the dry capsule weight.

8. The CAPSSHELL according to any one of claims 1 to 7, wherein the CAPSSHELL further comprises sucrose monolaurate.

9. The CAPSSHELL according to claim 8, wherein the CAPSSHELL contains 0.05 to 0.25% by weight of sucrose monolaurate, and the weight percentage is based on the dry capsule weight.

10. The CAPSSHELL according to any one of claims 1 to 9, wherein the CAPSSHELL further comprises sorbitan monolaurate.

11. The CAPSSHELL according to claim 10, wherein the CAPSSHELL contains 0.01 to 0.05% by weight of sorbitan monolaurate, and the weight percentage is based on the dry capsule weight.

12. The aforementioned CAPSSHELL is NaHCO 3 A capsshell according to any one of claims 1 to 11, further comprising:

13. The aforementioned CAPSSHELL is 0.02 to 0.06% by weight of NaHCO 3 The CAPSSHELL according to claim 12, comprising the above weight % based on the dry capsule weight.

14. The aforementioned CAPSSHELL contains pullulan, low acylgeran, high acylgeran, KCl, sucrose monolaurate, sorbitan monolaurate, and NaHCO3. 3 A capsshell according to any one of claims 1 to 13, comprising water.

15. The capsshell according to claim 14, wherein the capsshell contains at least 95% by weight of pullulan, the weight percentage being based on the weight of the capsshell.

16. A method for preparing a capsshell, The aforementioned CAPSSHEL is prepared by dip molding, A method which is a CAPSSHELL as defined in any one of claims 1 to 15.

17. A capsshell filled with activator AA, wherein AA is selected from drugs, pharmaceuticals, medicines, therapeutic agents, nutritional supplements, and active pharmaceutical ingredients. A CAPSSHELL, which is a CAPSSHELL as defined in any one of claims 1 to 15.

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