Icaritin tablet and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an icaritin tablet and a preparation method thereof. According to the tablet prescription, the problem of in-vitro dissolution of an indissolvable drug icaritin is solved, and compared with commercially available icaritin soft capsules, the tablet has greater advantages in manufacturing cost and production efficiency compared with a soft capsule dosage form. The tablet process is easy to implement and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an epimedium tablet and its preparation method. Background Technology

[0002] Icaritin, chemically known as 3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)-1,2-benzopyran-4-one, is a hydrolysis product of icariin, the main active ingredient in Epimedium. It possesses various pharmacological effects, including anti-inflammatory, antioxidant, antitumor, neuroprotective, and osteoprotective properties. On January 10, 2022, icariin soft capsules (Icaritin, ICT) received conditional marketing approval for the treatment of unresectable hepatocellular carcinoma in patients who are unsuitable for or refuse standard therapy and have never received systemic therapy.

[0003] However, due to the poor water solubility of icariin (<10μg / mL), its dosage form diversity is greatly limited, thus losing the advantage of different routes of administration; at the same time, the extremely low water solubility also results in low bioavailability of icariin, which greatly limits its clinical application and efficacy.

[0004] CN105982869B discloses an icariin tablet containing icariin, hydroxypropyl cellulose, fumed silica, diethylene glycol monoethyl ether, and other pharmaceutically acceptable excipients. The icariin is dissolved in diethylene glycol monoethyl ether, hydroxypropyl cellulose is added, and the mixture is stirred until dissolved. Fumed silica is then added for adsorption. Finally, the mixture is thoroughly mixed with the pharmaceutically acceptable excipients and compressed using a direct compression process. The applicant's previous research found that although icariin has good solubility in diethylene glycol monoethyl ether, the drug precipitates instantly when this solution is added to water. Inhibiting this precipitation is a key technical challenge for this invention. Furthermore, the tablet disclosed in CN105982869B requires a large amount of fumed silica, which could cause respiratory damage to workers and is detrimental to their health.

[0005] CN113368066B discloses an icariin tablet and its preparation method. The tablet contains icariin, low-melting-point excipients, microcrystalline cellulose, and pharmaceutically acceptable excipients. The low-melting-point excipients are polyethylene glycol or poloxamer. The microcrystalline cellulose is microcrystalline cellulose KG-802 or microcrystalline cellulose PH-102. The pharmaceutically acceptable excipients are disintegrants and lubricants. The disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, or low-substituted hydroxypropyl cellulose. The lubricant is selected from hydrogenated castor oil, sodium fumarate stearate, magnesium stearate, zinc stearate, or talc.

[0006] CN109718221B discloses an icariin preparation containing icariin, sodium carboxymethyl cellulose, and hydroxypropyl β-cyclodextrin.

[0007] Although the above-mentioned existing technologies disclose some tablets of icariin, their oral bioavailability, tablet stability and preparation process still do not meet expectations. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention employs micronization technology to prepare icariin tablets, with the aim of:

[0009] 1. Overcome the stability defects of existing commercially available dosage forms. The gelatin shell of icariin soft capsules is prone to cross-linking reactions during long-term storage, leading to delayed drug release and decreased bioavailability;

[0010] 2. Overcoming the limitations of the physical properties of raw materials, icariin belongs to BCS Class IV drugs (low solubility and low osmotic pressure), is insoluble in various pH media, and has an oral bioavailability of only 4.33%.

[0011] 3. Objectives of this invention: To achieve efficient in vitro dissolution (>80% within 60 minutes); to improve in vivo bioavailability, achieving bioequivalence with commercially available soft capsules; and to simplify the production process, reduce costs, and improve formulation stability by employing a wet granulation and tableting process.

[0012] The technical solution of the present invention is as follows:

[0013] An icariin tablet, by weight percentage, comprises 33.3% icariin, 0.5% solubilizer, 56.17% filler, 4% binder, 2.5% internal disintegrant, 2.5% external disintegrant, 0.5% glidant and 0.5% lubricant.

[0014] In some embodiments, the solubilizer is selected from SDS, poloxamer, and L-arginine, preferably SDS.

[0015] In some embodiments, the filler is selected from lactose, mannitol, and microcrystalline cellulose, preferably lactose.

[0016] In some embodiments, the disintegrant is selected from PVPP, CCNa, CMS-Na, and preferably CCNa.

[0017] In some embodiments, the adhesive is selected from hydroxypropyl cellulose, povidone VA64, and povidone K30, preferably povidone K30.

[0018] In some embodiments, the flow aid is selected from colloidal silica.

[0019] In some embodiments, the lubricant is selected from magnesium stearate.

[0020] An icariin tablet, comprising the following ingredients by weight percentage,

[0021] 33.3% icariin, 0.5% SDS, 56.17% lactose, 4% povidone K30, 2.5% internally added CCNa, 2.5% externally added CCNa, 0.5% colloidal silica and 0.5% magnesium stearate.

[0022] The present invention also provides a method for preparing the icariin tablets, comprising the following steps:

[0023] The prescribed amounts of epimedium, lactose, and CCNa were premixed in a granulation pan. Then, the SDS solution was uniformly atomized and sprayed into the granulation pan for granulation. The granules were wet-granulated through a sieve, dried, and then dry-granulated through a sieve. CCNa, magnesium stearate, and colloidal silica were added for total mixing, and finally, the mixture was compressed into tablets.

[0024] The beneficial effects of this invention are: 1. Advantages in in vitro dissolution: By using micronization technology combined with wet granulation process, the cumulative dissolution rate of icariin tablets can reach more than 80% within 60 minutes.

[0025] 2. The stability is relatively good. Results show that icariin tablets showed no significant changes under high temperature and light conditions, indicating relative stability. However, in a high humidity environment of RH 92.5%±5%, the moisture absorption weight gain exceeded 5%. Even when the humidity was reduced to RH 75%, the moisture absorption weight gain was within acceptable limits, but the icariin tablets still showed decreased hardness and cracking. The dissolution curve showed a slower trend, and the dissolution rate decreased. This indicates that humidity needs to be considered when storing icariin tablets. Attached Figure Description

[0026] Figure 1. Effect of different particle sizes of icariin raw material on dissolution (n=3)

[0027] Figure 2. Effect of different types of fillers on dissolution (n=3)

[0028] Figure 3. Effect of different types of disintegrants on dissolution (n=3)

[0029] Figure 4. Effect of different types of solubilizers on dissolution (n=3)

[0030] Figure 5. Effect of different types of binders on dissolution (n=3)

[0031] Figure 6. Effect of SDS dosage on the dissolution of icariin tablets (n=3)

[0032] Figure 7. Effect of CCNa dosage on the dissolution of icariin tablets (n=3)

[0033] Figure 8. Effect of povidone K30 dosage on the dissolution of icariin tablets (n=3)

[0034] Figure 9. Effect of the ratio of internal and external addition of CCNa on the dissolution of icariin tablets (n=3)

[0035] Figure 10 Comparative Examples 1 and 2, dissolution comparison with the tablets of the present invention Detailed Implementation

[0036] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0037] Example 1: Preliminary Screening of Prescriptions

[0038] The applicant has proposed the following preliminary prescription through preliminary experiments, and will optimize the prescription in the future.

[0039] Table 1 Preliminary Prescription

[0040] raw materials How to join Dosage (mg / tablet) percentage(%) effect Epimedium Nega 50 33.33 API L-arginine Nega 4.5 3 Solubilizer lactose Nega 83.5 55.67 filler Povidone K30 Nega 6.0 4 Adhesive CCNa Internal or external 4.5 3 Disintegrant colloidal silica Plus 0.75 0.5% retention aid magnesium stearate Plus 0.75 0.5% lubricant water / 2 / Wetting agent (removed upon drying) Total / 150 100 /

[0041] During the exploration of the preparation process, it was found that wet granulation produces particles with better flowability and greater uniformity, and can prevent powder from flying away. Therefore, this study intends to adopt the wet granulation process, and the specific steps are initially planned as follows:

[0042] (1) Pulverize the raw material to a specified particle size range;

[0043] (2) Wet granulation: Add lactose, API, L-arginine, povidone K30 and the internally added CCNa into a wet granulator, mix evenly, and add pure water for granulation;

[0044] (3) Granulation: The wet granules are granulated by passing them through a square hole screen, initially selecting 1.5 mm * 1.5 mm;

[0045] (4) Drying: Drying is carried out using a fluidized bed or oven until the moisture content of the material is less than 3.0%;

[0046] (5) Dry granulation: The dry granules are granulated by passing them through a round hole sieve, initially selecting 1.0 mm * 1.0 mm;

[0047] (6) Mixing: Weigh the dry particles, calculate the amount of colloidal silica, magnesium stearate and CCNa added based on the yield of dry particles, and mix them.

[0048] (7) Tableting: Select a suitable die for tableting, and set the tablet weight as 150 mg ± 7.5 mg.

[0049] Example 2: Preliminary screening of particle size of icariin raw material

[0050] This embodiment screened the particle size of icariin raw material. An air jet mill was used to micronize the icariin raw material particle size (D90) to below 10 μm. Small-scale batch preparations were then carried out using the same wet granulation process as before micronization. The results are shown in Figure 1, indicating that micronization technology significantly improves dissolution. Further research will focus on icariin raw materials with a D90 less than 10 μm.

[0051] Example 3: Effect of filler type on the dissolution of icariin tablets

[0052] Based on the aforementioned preliminary formulation and process, the type of filler was changed, and the effects of three different fillers—lactose, mannitol, and microcrystalline cellulose—on the dissolution of icariin under the same dissolution conditions were investigated. The results are shown in Figure 2. The results show that when lactose was used as the filler, both the dissolution rate and the final dissolution plateau were superior to the other two fillers. For the poorly soluble icariin, lactose was unexpectedly found to be a soluble filler with a fast dissolution rate, which can further increase the specific surface area of ​​the API in contact with the medium, thereby promoting solubility. Therefore, lactose was selected as the filler for icariin tablets.

[0053] Example 4: Effect of disintegrant type on the dissolution of icariin tablets

[0054] Based on the aforementioned preliminary formulation and process, the effects of different disintegrants—PVPP, CCNa, and CMS-Na—on the dissolution of icariin tablets were investigated. (See Figure 3). The results show that CCNa has a better dissolution rate and cumulative dissolution amount than PVPP and CMS-Na. Compared with the other two disintegrants, CCNa exhibits both capillary and swelling disintegration mechanisms for icariin tablets, demonstrating superdisintegration even in very small amounts. Therefore, CCNa was selected as the disintegrant for icariin tablets.

[0055] Example 5: Effect of Solubilizer Type on the Dissolution of Epimedium Tablets

[0056] Based on the aforementioned preliminary formulation and process, the types of solubilizers were varied, and the effects of SDS, poloxamer, and L-arginine on the dissolution of icariin tablets were investigated. The results are shown in Figure 4. SDS, as a solubilizer, showed superior dissolution rate and cumulative dissolution compared to the other two solubilizers. Under the same dissolution conditions, the dissolution plateau was reached within 60 minutes. This indicates that SDS is the most effective solubilizer, and SDS will be used as the solubilizer in future applications.

[0057] Example 6: Effect of adhesive type on the dissolution of icariin tablets

[0058] Based on the aforementioned preliminary formulation and process, the type of binder was changed, and hydroxypropyl cellulose, povidone VA64, and povidone K30 were investigated. The dissolution results are shown in Figure 5. It can be seen that the dissolution plateau of hydroxypropyl cellulose as a binder is significantly lower than that of povidone VA64 and povidone K30. Furthermore, during the tableting process, the drug hardness significantly decreased when hydroxypropyl cellulose was used as a binder, while using povidone VA64 as a binder resulted in sticking and punching problems. Therefore, povidone K30 was the most suitable binder.

[0059] Example 7: Effect of SDS dosage on the dissolution of icariin tablets

[0060] After confirming the types of excipients, the effect of different amounts of solubilizer SDS (0 mg, 0.75 mg, and 1.5 mg) on ​​the dissolution of icariin tablets was further investigated. The specific dissolution results are shown in Figure 6. The results showed that without the addition of SDS, the dissolution rate was slower and the plateau period was shorter. When the SDS dosage was increased to 0.75 mg, compared to 1.5 mg and 0 mg, the dissolution rate was the fastest and the cumulative dissolution amount was the highest. Therefore, 0.75 mg was selected as the dosage of SDS in icariin tablets.

[0061] Example 8: Effect of CCNa dosage on the dissolution of icariin tablets

[0062] Based on the adjusted formulation after determining the types of excipients, the effect of different dosages of CCNa as a disintegrant—1.5 mg, 4.5 mg, and 7.5 mg—on the dissolution of icariin tablets was further investigated. The results are shown in Figure 7. The results indicate that the dosage of CCNa has a significant impact on the dissolution of icariin tablets; the amount of icariin dissolved increases with increasing CCNa dosage, with the highest cumulative dissolution over 60 minutes at a dosage of 7.5 mg. Therefore, 7.5 mg was selected as the dosage of CCNa in icariin tablets.

[0063] Example 9: Effect of Povidone K30 Dosage on the Dissolution of Epimedium Tablets

[0064] Based on the adjusted formulation after determining the types of excipients, the effect of different dosages of povidone K30 as a binder (2 mg, 4 mg, and 6 mg) on ​​the dissolution of icariin tablets was further investigated. The results are shown in Figure 8. The results indicate that the dosage of povidone K30 did not significantly affect the dissolution plateau of icariin tablets, but the dissolution rate of icariin increased with increasing povidone K30 dosage. During the preparation process, the tablets compressed with 6 mg of povidone K30 exhibited higher hardness and did not crack; therefore, 6 mg was selected as the dosage of povidone K30 in the formulation.

[0065] Example 10 Effect of CCNa internal and external addition ratio on the dissolution of icariin tablets

[0066] Based on the adjusted formulation after determining the types of excipients, the effect of different internal and external disintegrant ratios of CCNa as a disintegrant on the dissolution of icariin tablets was further investigated. The internal and external disintegrant ratio significantly affected the dissolution effect of the formulation, especially for poorly soluble drugs. External disintegrants accelerated tablet disintegration, while internal disintegrants raised the dissolution plateau. A reasonable internal and external disintegrant ratio could significantly improve tablet dissolution performance. The dissolution results are shown in Figure 9. The results showed that the cumulative dissolution was highest when the internal and external disintegrant ratio of CCNa was 1:1. Therefore, an internal and external disintegrant ratio of 1:1 was selected for the subsequent preparation of icariin tablets.

[0067] The final prescription for Epimedium tablets is shown in the table below.

[0068]

[0069] The process conditions were determined as follows: The prescribed amounts of epimedium, lactose, and CCNa were premixed in a granulation pan for 5 minutes. Then, the SDS solution was uniformly atomized and sprayed into the granulation pan. After spraying, granulation was carried out for 3 minutes. The granules were then wet-granulated through a 1.5 mm * 1.5 mm sieve, dried to a moisture content below 3%, and dry-granulated through a 1.0 mm * 1.0 mm sieve. CCNa, magnesium stearate, and colloidal silica were added and mixed together. Finally, the mixture was tableted.

[0070] Pharmacokinetic Study of Epimedium Tablets in Beagle Dogs

[0071] In vivo pharmacokinetic experimental design for beagle dogs

[0072] A single-dose, two-period, two-crossover experimental design was used. Six Beagle dogs were randomly divided into two groups, each group...

[0073] Three Beagle dogs were fasted for 12 hours before administration and the medication was taken with 50 ml of warm water. The test formulation was icariin tablets (50 mg).

[0074] The reference formulation was commercially available icariin soft capsules (100 mg), of which 4 tablets of self-made icariin tablets were administered, and commercially available icariin...

[0075] Two soft capsules were administered. Healthy adult beagle dogs were fasted for 12 hours prior to the experiment (free access to water was permitted).

[0076] Blank blood samples were collected via forelimb vein before administration (0 h), and oral intake resumed 4 h after administration. Throughout the trial, [the following data was collected] compared to [previous data].

[0077] The dog can drink water freely. After medication, blood was collected at various time points (0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, ...).

[0078] Blood samples of 2 ml were collected from the veins of the forelimbs of Beagles at 8, 10, 12, 24, and 36 hours. After blood collection, the sample was immediately placed in a container containing...

[0079] Centrifuge in a centrifuge tube containing 30 μL of 3% heparin sodium solution (8000 rpm for 5 min), then rapidly extract plasma.

[0080] Transfer to a -80°C freezer for storage. A 7-day washout period is set between two dosing cycles to ensure complete drug elimination.

[0081] The contents are shown in Table 2.

[0082] Table 2. Pharmacokinetic Information in Beagle Dogs

[0083]

[0084] Table 3 Comparison of pharmacokinetic parameters of icariin tablets and icariin soft capsules (G1 level).

[0085]

[0086] Table 4 Comparison of pharmacokinetic parameters of icariin tablets and icariin soft capsules (G3)

[0087]

[0088] Pharmacokinetic parameters were calculated using the Winnolin 8.1 non-compartmental model (NCA) software. The main evaluation index was C. max ,

[0089] AUC 0-t and AUC 0-∞ The remaining parameters are secondary evaluation indicators.

[0090] Specific results are shown in Tables 3 and 4. After administration of the reference preparation, icariin soft capsules, the peak time of G1 metabolite was 1.292 ± 0.954 h, C max The concentration was 14.694 ± 4.896 ng / mL, and the AUC was... 0-t The concentration was 59.529±54.254 h·ng / mL, the half-life was 6.876±3.25 h, and the clearance rate was 4379114.586±1620180.254 mL / h; the peak time of G3 metabolite was 1.458±0.928 h, and the C max The concentration was 205 ± 63.652 ng / mL, and the AUC was... 0-tThe concentration was 949.946±721.758 h·ng / mL, the half-life was 5.225±4.381 h, and the clearance rate was 263633.806±114180.542 mL / h.

[0091] The peak time of G1 metabolite after administration of the test formulation, icariin tablets, was 0.75 ± 0.387 h. max The concentration was 18.71 ± 8.643 ng / mL, and the AUC was... 0-t The concentration was 52.248±37.186 h·ng / mL, the half-life was 8.501±3.241 h, and the clearance rate was 4785369.115±2127923.446 mL / h; the peak time of G3 metabolite was 1.042±0.51 h, and the C max The concentration was 181.4 ± 84.948 ng / mL, with an AUC of 181.4 ± 84.948 ng / mL. 0-t The concentration was 675.457 h·ng / mL, the half-life was 3.116±0.747 h, and the clearance rate was 343336.602±166722.733 mL / h. Pharmacokinetic parameters of the G1 and G3 metabolites showed that the Tmax of the self-made icariin tablets was generally faster than that of the reference formulation.

[0092] This invention uses commercially available icariin soft capsules as the reference formulation and icariin tablets as the test formulation to conduct pharmacokinetic studies of icariin tablets and icariin soft capsules in beagle dogs, measuring blood drug concentrations and calculating pharmacokinetic parameters. According to the statistical results of G1 and G3, there were no significant differences in the main pharmacokinetic parameters between icariin tablets and icariin soft capsules.

[0093] Comparing icariin tablets and soft capsules, tablets offer significant advantages in manufacturing cost and production efficiency. Furthermore, soft capsules contain gelatin, which is prone to cross-linking reactions in stability tests, affecting both in vitro dissolution and in vivo release. Additionally, the sourcing of gelatin (often from pigskin) can impact sales in certain regions. Therefore, under bioequivalence conditions, icariin tablets have a greater advantage over soft capsules.

[0094] Comparative Example 1

[0095] Icariin tablets were prepared according to the prescription and process described in CN105982869B.

[0096] Comparative Example 2

[0097] Icariin tablets were prepared according to the prescription and process described in CN113368066B.

[0098] The dissolution of the tablets of this application and the tablets of Comparative Examples 1 and 2 were tested under the same conditions, and the results are as follows: Figure 10 As shown, the results indicate that the tablets of this application dissolve well.

Claims

1. An icariin tablet, comprising, by weight percentage, 33.3% icariin, 0.5% solubilizer, 56.17% filler, 4% binder, 2.5% internal disintegrant, 2.5% external disintegrant, 0.5% glidant and 0.5% lubricant.

2. The tablet according to claim 1, characterized in that, The solubilizer is selected from SDS, poloxamer, and L-arginine, with SDS being preferred.

3. The tablet according to claim 1, characterized in that, The filler is selected from lactose, mannitol, and microcrystalline cellulose, with lactose being preferred.

4. The tablet according to claim 1, characterized in that, The disintegrant is selected from PVPP, CCNa, and CMS-Na, preferably CCNa.

5. The tablet according to claim 1, characterized in that, The adhesive is selected from hydroxypropyl cellulose, povidone VA64, and povidone K30, with povidone K30 being preferred.

6. The tablet according to claim 1, characterized in that, The flow aid is selected from colloidal silica.

7. The tablet according to claim 1, characterized in that, The lubricant is selected from magnesium stearate.

8. The tablet according to claim 1, characterized in that, An icariin tablet, comprising the following ingredients by weight percentage, 33.3% icariin, 0.5% SDS, 56.17% lactose, 4% povidone K30, 2.5% internally added CCNa, 2.5% externally added CCNa, 0.5% colloidal silica and 0.5% magnesium stearate.

9. The method for preparing the icariin tablets according to claim 1, comprising the following steps: The prescribed amounts of epimedium, lactose, and CCNa were premixed in a granulation pot; then, the SDS solution was uniformly atomized and sprayed into the granulation pot for granulation; wet granulation was performed by passing the granules through a sieve, and then the granules were dried and dry granulated by passing them through a sieve. CCNa, magnesium stearate, and colloidal silica were added for total mixing, and finally, tableting was performed.

Images