Apremilast buffering agent tablet composition and preparation method thereof

Abstract

The invention relates to an apremilast buffer tablet composition and a preparation method thereof. The apremilast buffer tablet composition comprises apremilast, a buffer, a chelating agent, a diluent, an adhesive, a disintegrating agent and a lubricant. The pH value is adjusted to 6.8-7.4 by a buffering agent, and tabletting is carried out by adopting a direct tabletting method. The apremilast composition has the advantages that the formula and the preparation method are reasonable in design, the seed buffer component is introduced into the apremilast composition, so that the stability and the solubility of apremilast can be effectively improved, the apremilast is completely released in an in-vitro release test, and the medicine can be ensured to be completely dissolved in the stomach and not degraded in the absorption process.

Description

Technical Field

[0001] The present invention relates to an Apremilast composition and a preparation method thereof, and in particular to an Apremilast tablet composition containing a buffer and a preparation method thereof. Background Art

[0002] Apremilast is a white to pale yellow powder that is generally used in tablet form to treat plaque psoriasis and psoriatic arthritis.

[0003] According to literature reports, Apremilast and its preparations are extremely unstable in alkaline environments and degrade very quickly. In addition, slight degradation will occur in a strong acidic degradation environment.

[0004] Apremilast belongs to BCS IV grade and has very low solubility in water. The solubility increases with the increase of pH value of the dissolution medium. Therefore, when the tablet disintegrates and dissolves, the pH value of the dissolution medium is more important for the better dissolution of Apremilast. The solubility at pH 6.8 and 7.4 is 16.22 micrograms and 22.84 micrograms per milliliter, respectively. That is, Apremilast will degrade under acidic and alkaline conditions, and it will degrade faster under alkaline conditions with a pH of 7.4.

[0005] The disintegration, dissolution and stability of the drug substance in the tablet are the key to the safety and effectiveness of the preparation. Considering stabilizing Apremilast under neutral conditions to solve its degradation problem, there is no relevant record in the prior art. Summary of the invention

[0006] The present invention provides an Apremilast buffer tablet composition and a preparation method thereof, the purpose of which is to overcome the above-mentioned deficiencies in the prior art and improve the stability and solubility of Apremilast.

[0007] The technical solution of the present invention is an apremilast buffer tablet composition, the formula of which includes apremilast and a buffer or a combination of multiple buffers, which can enhance the stability and solubility of apremilast.

[0008] Preferably, the formulation further comprises a chelating agent or a combination of multiple chelating agents.

[0009] Preferably, the formulation further comprises a diluent or a combination of multiple diluents, a binder or a combination of multiple binders, a disintegrant or a combination of multiple disintegrants, and a lubricant or a combination of multiple lubricants.

[0010] Preferably, the buffer is adjusted to a pH value of 6.8-7.4, the chelating agent is selected from disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, diethylenetriaminepentaacetic acid and sodium glutamate diacetate, the diluent is selected from lactose monohydrate, modified starch and mannitol, the binder is selected from microcrystalline cellulose, starch, pregelatinized starch, PEG, sorbitol and HPMC, the disintegrant is selected from sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, anhydrous lactose, and the lubricant is selected from talc, magnesium stearate and stearic acid.

[0011] Preferably, the buffer is citric acid and disodium hydrogen phosphate, the chelating agent is disodium edetate, the diluent is lactose monohydrate, the binder is microcrystalline cellulose, the disintegrant is cross-linked sodium carboxymethyl cellulose, and the lubricant is magnesium stearate.

[0012] Preferably, each tablet of the apremilast buffer tablet composition is composed of the following ingredients: 10-30 mg of apremilast, 80-100 mg of lactose monohydrate, 30-50 mg of microcrystalline cellulose; 4-6 mg of cross-linked sodium carboxymethyl cellulose, disodium hydrogen phosphate and citric acid in an amount sufficient to adjust the pH value of the tablet to 6.8-7.4 when dissolved in water, 1-3 mg of disodium edetate, and 0.5-2 mg of magnesium stearate.

[0013] Preferably, the preparation method of the apremilast buffer tablet composition adopts a direct tableting method.

[0014] Preferably, during preparation, apremilast, lactose monohydrate, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, disodium edetate, citric acid and disodium hydrogen phosphate are mixed using a suitable stirrer, stearic acid is added and mixed, and then the mixture is tableted using a rotary tablet press.

[0015] The advantages of the present invention are as follows: the formula and the preparation method are reasonably designed; by introducing a buffer component into the Apremilast composition, the stability and solubility of Apremilast can be effectively improved; complete release is shown in an in vitro release test; and it can be ensured that the drug is completely dissolved in the stomach and is not degraded during the absorption process. DETAILED DESCRIPTION

[0016] The present invention is further described in detail below with reference to examples and specific implementation modes.

[0017] A buffer tablet composition of Apremilast, comprising Apremilast or any pharmaceutically acceptable salt thereof, a buffer or a combination of multiple buffers, a chelating agent or a combination of multiple chelating agents, and a combination of other appropriate ingredients for preparations, which can enhance the stability and solubility of Apremilast.

[0018] As an example, other suitable combinations of ingredients for the formulation include one diluent or a combination of multiple diluents, one binder or a combination of multiple binders, one disintegrant or a combination of multiple disintegrants, and one lubricant or a combination of multiple lubricants.

[0019] As a further example, the buffer can adjust the pH value to about 6.8-7.4, the chelating agent is selected from disodium ethylenediaminetetraacetic acid, dipotassium ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid and sodium glutamate diacetate, the diluent is selected from lactose monohydrate, modified starch and mannitol, the binder is selected from microcrystalline cellulose, starch, pregelatinized starch, PEG, sorbitol and HPMC, the disintegrant is selected from sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, anhydrous lactose, and the lubricant is selected from talc, magnesium stearate and stearic acid.

[0020] As a further embodiment, the buffer is citric acid and disodium hydrogen phosphate, the chelating agent is disodium edetate, the diluent is lactose monohydrate, the binder is microcrystalline cellulose, the disintegrant is cross-linked sodium carboxymethyl cellulose, and the lubricant is magnesium stearate. The combination of citric acid, disodium hydrogen phosphate and disodium edetate can adjust the pH value to about 6.8-7.4 to improve the stability and solubility of Apremilast.

[0021] The preparation method of the above apremilast buffer tablet composition is to adopt a direct tableting method or a dry granulation tableting method.

[0022] As an embodiment, the ingredients in the formula are mixed by a suitable mixing method and then tableted.

[0023] As a further embodiment, each tablet of the apremilast buffer tablet composition is composed of the following ingredients: 10-30 mg of apremilast, 80-100 mg of lactose monohydrate, 30-50 mg of microcrystalline cellulose; 4-6 mg of cross-linked sodium carboxymethyl cellulose, disodium hydrogen phosphate and citric acid in an amount sufficient to adjust the pH value of the tablet to about 6.8-7.4 when dissolved in water, 1-3 mg of disodium edetate, and 0.5-2 mg of magnesium stearate.

[0024] As a further example, lactose monohydrate is H, microcrystalline cellulose is a pharmaceutical 112, cross-linked carboxymethyl cellulose sodium is Ac-d i-sol, magnesium stearate is Li gamed MF, disodium hydrogen phosphate is

[0025] As a further example, during preparation, apremilast, lactose monohydrate, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose are mixed using a suitable stirrer, stearic acid is added and mixed, and then the mixture is tableted using a rotary tablet press.

[0026] Comparative Example

[0027]

[0028] Table 1: Comparative Example Formula Composition

[0029] Preparation of Apremilast Tablets by Direct Compression:

[0030] [a] Packaging: Pack each ingredient separately in a suitable polyethylene bag and seal tightly after packaging.

[0031] [b] Sieving: Use an electric sieve to separate apremilast and lactose monohydrate. H], microcrystalline cellulose [Pharmace 112] and cross-linked sodium carboxymethylcellulose [Ac-di-sol] were passed through a 30-mesh sieve one by one, and then the mixture was collected in a suitable polyethylene bag.

[0032] [c] Mixing: Transfer the mixture to a suitably sized blender and mix at 5-25 RPM for 10-20 minutes.

[0033] [d] Lubrication: Sieve magnesium stearate [Li gamed MF] with a 60-mesh sieve, add it to the mixer in step [c], and stir at a speed of 5-25 RPM for 10-20 minutes.

[0034] [e] Tableting: The mixed powder is formed into tablets using a rotary tablet press and suitable type B molds.

[0035] Example 1

[0036]

[0037]

[0038] Table 2: Example formulation composition

[0039] Preparation of Apremilast Tablets by Direct Compression:

[0040] The difference from the comparative example is that step [b] also uses an electric sifter to separate disodium hydrogen phosphate Citric acid and disodium EDTA were passed through a 30-mesh sieve one by one and mixed with other ingredients.

[0041] Example 2: Dissolution Study

[0042] The tablets were subjected to dissolution studies using 0.1 N hydrochloric acid using a USP Apparatus II (paddle type) at 60 RPM, 900 mL capacity, with sampling time points of 10, 15, 20, 30, 45, and 60 minutes.

[0043]

[0044] Table 3: Dissolution study results

[0045] The results are shown in the table above, indicating that the buffered formulation of Example 1 can completely release the drug compared to the comparative formulation, which is due to the increased solubility of the drug.

[0046] Example 3: Solubility studies

[0047] To understand the effect of apremilast on degradation products in acidic, alkaline, and buffered solutions, tablet solutions without added buffer were kept for 12 h.

[0048]

[0049] Table 4: Solubility study results

[0050] The results are shown in the table above, indicating that the improved formulation of Example 1 is more stable than under acidic or alkaline conditions.

[0051] Example 4: Tablet Stability Study

[0052] The tablets were tested for stability over a 12-month period under room temperature storage conditions.

[0053]

[0054]

[0055] Table 5: Stability study results

[0056] The results showed that the buffered tablet formulation had improved stability compared to the control formulation.

[0057] In summary, the buffered formulation of the embodiment has improved solubility and stability of Apremilast at a specific pH value, and thus has better safety and efficacy when administered to the human body.

[0058] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all fall within the protection scope of the present invention.

Claims

1. An Apremilast buffer tablet composition, characterized in that: The formulation includes apremilast and a buffer or a combination of buffers.

2. The apremilast buffer tablet composition according to claim 1, characterized in that: The formulation also includes a chelating agent or a combination of chelating agents.

3. The apremilast buffer tablet composition according to claim 2, characterized in that: The formulation also includes one diluent or a combination of multiple diluents, one binder or a combination of multiple binders, one disintegrant or a combination of multiple disintegrants, and one lubricant or a combination of multiple lubricants.

4. The apremilast buffer tablet composition according to claim 3, characterized in that: The buffer is used to adjust the pH value to 6.8-7.4, the chelating agent is selected from disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, diethylenetriaminepentaacetic acid and sodium glutamate diacetate, the diluent is selected from lactose monohydrate, modified starch and mannitol, the binder is selected from microcrystalline cellulose, starch, pregelatinized starch, PEG, sorbitol and HPMC, the disintegrant is selected from sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and anhydrous lactose, and the lubricant is selected from talc, magnesium stearate and stearic acid.

5. The apremilast buffer tablet composition according to claim 4, characterized in that: The buffer is citric acid and disodium hydrogen phosphate, the chelating agent is disodium ethylenediaminetetraacetate, the diluent is lactose monohydrate, the binder is microcrystalline cellulose, the disintegrant is cross-linked sodium carboxymethyl cellulose, and the lubricant is magnesium stearate.

6. The apremilast buffer tablet composition according to claim 5, characterized in that: Each apremilast buffer tablet composition is composed of the following ingredients: 10-30 mg of apremilast, 80-100 mg of lactose monohydrate, 30-50 mg of microcrystalline cellulose, 4-6 mg of cross-linked sodium carboxymethyl cellulose, disodium hydrogen phosphate and citric acid in amounts sufficient to adjust the pH value of the tablet to 6.8-7.4 when dissolved in water, 1-3 mg of disodium ethylenediaminetetraacetic acid, and 0.5-2 mg of magnesium stearate.

7. A method for preparing an Apremilast buffer tablet composition according to any one of claims 3 to 6, characterized in that: Direct tableting method is used.

8. The method for preparing an Apremilast buffer tablet composition according to claim 7, characterized in that: During the preparation, apremilast, buffer, chelating agent, diluent, binder and disintegrant are mixed by using a suitable stirrer, and then a lubricant is added and mixed, and then the mixture is tableted by using a rotary tablet press.

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