CN112245403B

CN112245403B - Phosphodiesterase-4 inhibitor and oral solid composition thereof

Info

Publication number: CN112245403B
Application number: CN202011167722.8A
Authority: CN
Inventors: 唐建飞; 郭艳超; 马雯霞; 张婧; 赵福斌; 关廷军; 陈宣其
Original assignee: Hangzhou Zhuyangxin Pharmaceutical Co ltd
Current assignee: Hangzhou Zhuyangxin Pharmaceutical Co ltd
Priority date: 2020-10-23
Filing date: 2020-10-28
Publication date: 2022-04-22
Anticipated expiration: 2040-10-28
Also published as: CN112245403A

Abstract

The invention relates to a phosphodiesterase-4 inhibitor and an oral solid composition thereof, wherein the composition is an apremilast tablet and comprises the following components: apremilast, lactose, microcrystalline cellulose, magnesium stearate, and the like. The tablet is prepared by a method comprising the following steps: uniformly mixing apremilast, lactose, microcrystalline cellulose and the like, and preparing granules by a dry method by using a compression roller device; adding the balance of croscarmellose sodium into the obtained granules, uniformly mixing, then adding magnesium stearate, and uniformly mixing; tabletting the obtained mixed granules on a tabletting machine to obtain tablets in a plain tablet form; optionally coating the obtained plain tablets with a coating solution to obtain coated tablets. The tablets of the invention can be used for the treatment of adult patients with active psoriatic arthritis, adult patients with moderate to severe plaque psoriasis who are suitable for phototherapy or systemic therapy, adult patients with oral ulcers associated with behcet's disease; and the tablet exhibits excellent technical effects as described in the specification.

Description

Phosphodiesterase-4 inhibitor and oral solid composition thereof

Technical Field

The invention belongs to the technical field of medicines, relates to a selective phosphodiesterase-4 inhibitor for oral administration, and particularly relates to a selective phosphodiesterase-4 inhibitor oral pharmaceutical composition taking apremilast as an active substance. The pharmaceutical composition can be used for treating adult patients with active psoriatic arthritis, adult patients with moderate to severe plaque psoriasis suitable for phototherapy or systemic therapy, and adult patients with oral ulcer related to Behcet's disease.

Background

Psoriasis is commonly called as psoriasis, is a chronic inflammatory skin disease, has long course of disease and easy recurrence tendency, and some cases are not cured almost for the whole life. The disease is mainly developed in young and old years, and has great influence on the physical health and mental conditions of patients. Clinically, the red papules or plaques are covered with a plurality of layers of silvery-white scales which are better developed on the extending sides of the limbs, the scalp and the back, and severe skin damage can cause the whole body to develop and can cause high fever, pustules, red skin disease-like changes and large and small arthrosis of the whole body.

Although many studies have been made on the etiology of psoriasis, the pathogenesis has not yet been elucidated, and psoriasis is now considered to be an immune-mediated genetic skin disease. Clinical heterogeneity and obvious polygenic genetic patterns indicate that the combined action of many factors is involved in the development of diseases. For example, genetic factors, a significant proportion of patients have a familial history of disease, and some families have a significant genetic predisposition. Generally, the family history accounts for about 30%. The incidence varies widely among different races. Psoriasis is a polygenic genetic disease with interaction of various factors such as genetic factors and environmental factors. The incidence of certain HLA antigens is obviously increased in patients with the disease. The psoriasis and other diseases (such as rheumatoid arthritis, atopic dermatitis and the like) have possible overlapping genetic loci, all of which indicate that the psoriasis is a polygenic hereditary disease, the accumulation of the effects of a plurality of genes reaches a certain threshold value, and environmental factors can promote the occurrence of the diseases. As another example, infection factors, many scholars have demonstrated that streptococcal infection is associated with the onset and duration of psoriasis in humoral immunity (anti-streptococcal group), cellular immunity (peripheral blood and cutaneous T cells), bacterial culture and therapy. In psoriasis patients, staphylococcus aureus infections can aggravate skin lesions, which are associated with superantigens of staphylococcus aureus exotoxins. Although the occurrence of the disease has a certain relationship with the infection of viruses (such as HIV virus) and fungi (such as malassezia), the exact mechanism of the disease has not been finally confirmed. As another example, immune factors, including humoral and cellular immunity, there is a great deal of evidence that psoriasis is an immune-mediated disease in which helper T lymphocytes and their secreted cytokines play a very important role, the close relationship of certain HLA antigens to psoriasis and the invasion of mononuclear cells before epidermal proliferation to form plaques, and the therapeutically significant effect of the selective cellular immunosuppressive agent cyclosporin is an immune-mediated inflammatory disease. Most scholars now believe that helper T lymphocytes play a major role in the development of psoriasis.

Apremilast, CAS registry number 608141-41-9, having a chemical name: n- [2- [ (1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl ] -2, 3-dihydro-1, 3-dioxo-1H-isoindol-4-yl ] acetamide, of the formula: C22H24N2O7S, molecular weight 460.5, its chemical structural formula is as follows:

apremilast is an initiated oral selective phosphodiesterase-4 inhibitionAgents approved by FDA 3 months in 2014, EMA 1 months in 2015 and PMDA 12 in 2016 for adult patients with active psoriatic arthritis, adult patients with moderate to severe plaque psoriasis who are eligible for phototherapy or systemic therapy, and Behcet's disease (R) ((R))

Disease) in adult patients with oral ulcers. The dosage form is tablet, and the specification is 10mg, 20mg and 30 mg. The drug was the first oral drug approved for the treatment of psoriasis in the last 20 years and was also the first oral drug approved for psoriatic arthritis in the last 15 years.

Apremilast is an oral small molecule phosphodiesterase 4(PDE4) inhibitor that inhibits cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in elevated intracellular cAMP levels. The specific mechanism by which apremilast exerts its therapeutic effect is not clear for psoriatic arthritis patients and psoriatic patients, the likely mechanism being that psoriasis is considered a Th 1-mediated autoimmune skin disease as it involves the pro-inflammatory cytokines IFN- γ, TNF- α. Apremilast is a small molecule phosphodiesterase 4(PDE4) inhibitor, with a semi-inhibitory concentration (IC50) of 74nmol/L inhibiting PDE-4 isolated from human monocytes U937, PDE4 being a cyclic adenosine monophosphate (cAMP) specific PDE, cAMP monophosphate being a key second messenger that regulates inflammatory responses, helps to maintain homeostasis by regulating the network of pro-and anti-inflammatory mediators, cAMP is regulated by intracellular Phosphodiesterases (PDEs), being the only way to degrade cAMP to AMP, thus increasing pro-inflammatory mediator production and decreasing anti-inflammatory mediator production. PDEs constitute at least 11 enzyme families based on amino acid sequence homology, sensitivity to inhibitors, and biochemical properties. Each enzyme within the PDE4 family targets its degraded cAMP and constitutes 4 subtypes (PDE4A through PDE4D) which are localized in the brain and in immunocompetent cells such as neutrophils, T lymphocytes, macrophages and eosinophils. Within this group, the PDE4 family (4-gene enzyme) plays a key role in degrading cAMP in inflammatory cells as well as endothelial cells, smooth muscle cells and keratinocytes.

CN107115310A (application number: 201710238204.2, Aige) discloses an apremilast oral solid preparation and a preparation method thereof, belonging to the field of pharmaceutical preparations. The apremilast oral solid preparation comprises a pharmaceutical active ingredient, a filler, a disintegrant, a lubricant and a coating material. The invention improves the flowability of the medicine with poor compressibility by adopting auxiliary materials, and prepares the oral solid preparation with good dissolution and stable quality by using a direct powder tabletting process. The preparation method has the advantages of simple operation, low production cost, high efficiency and environmental protection, and is suitable for the industrial mass production of the apremilast oral solid preparation.

CN105343025A (application No. 201510749073.5, Baishun) discloses an apremilast oral preparation and a preparation method thereof, wherein the apremilast oral preparation comprises the following components in percentage by weight: 2 to 20 percent of active ingredient apremilast, 20 to 70 percent of filling agent, 3 to 30 percent of disintegrating agent, 1 to 10 percent of adhesive, 0.2 to 5 percent of lubricant and 2 to 6 percent of coating material. The apremilast oral preparation prepared by the invention is believed to have the dissolution rate of more than 95 percent, high bioavailability, stable and reliable quality and great market development prospect, and overcomes the defects of poor solubility and low bioavailability of active ingredients.

CN104546831A (application No. 201410839155.4, new bosch) discloses a pharmaceutical composition containing apremilast, which contains apremilast and cyclodextrin or a cyclodextrin derivative. The invention is believed to improve the solubility of apremilast and increase the stability of the product by preparing the apremilast and the cyclodextrin or the cyclodextrin derivative into an inclusion compound.

CN109925292A (application No. 201711364730.X, Sancheng) discloses an Apremilast solid composition which comprises the following components in percentage by weight: 5% -14% of Apremilast; 82% -90% of a filling agent; 1 to 1.5 percent of disintegrating agent; 0.5 to 1 percent of lubricant; 2 to 6 percent of coating material. The apremilast solid composition prepared by the method is believed to have the dissolution rate of over 95 percent, high bioavailability, stable and reliable quality and wide clinical application prospect.

CN110548015A (application No. 201810540902.2, affluent) discloses an apremilast tablet, which comprises: active ingredients, excipients; the active ingredients account for 5-15% of the mass of the tablet; the excipient comprises an excipient A, and the excipient A is selected from one or a mixture of more of lactose, microcrystalline cellulose, Ludipress and Ludipress LCE; the excipient A accounts for 80-92% of the weight of the plain tablets, and is further selected from 85-90%; the preparation method comprises the following steps: pulverizing the active ingredients, and keeping the particle size distribution d (0.9) of the pulverized active ingredients less than or equal to 15.0 mu m for later use; sieving excipient for use; sieving active ingredients and excipient, and mixing; tabletting and coating. The apremilast tablet and the preparation method thereof are believed to greatly increase the dissolution rate of apremilast in the tablet, and the preparation method is simple and controllable in preparation process, environment-friendly, sustainable, low in production cost, high in production efficiency and suitable for large-scale industrial production.

However, there remains a need in the art for new methods for preparing oral solid pharmaceutical compositions of apremilast, such as for preparing oral tablets of apremilast having one or more advantageous properties.

Disclosure of Invention

The object of the present invention is to provide an oral tablet pharmaceutical composition of apremilast which is expected to exhibit one or more excellent properties. It has been surprisingly found that one or more excellent technical effects are obtained by preparing an oral tablet pharmaceutical composition of apremilast using the method of the invention, and the invention has been completed based on such findings.

To this end, the invention provides, in a first aspect, an apremilast tablet comprising the following components:

10 parts by weight of apremilast, 45-65 parts by weight of lactose (such as an anhydride or monohydrate thereof), 15-30 parts by weight of microcrystalline cellulose, 2-4 parts by weight of croscarmellose sodium, and 0.5-1 part by weight of magnesium stearate.

An apremilast tablet according to the first aspect of the invention, comprising the following components: 10 parts by weight of apremilast, 50-65 parts by weight of lactose (such as an anhydride or monohydrate thereof), 20-30 parts by weight of microcrystalline cellulose, 2-4 parts by weight of croscarmellose sodium, and 0.5-1 part by weight of magnesium stearate.

An apremilast tablet according to the first aspect of the invention, comprising the following components: 10 parts by weight of apremilast, 55-62 parts by weight of lactose (such as an anhydrate or monohydrate thereof), 22-28 parts by weight of microcrystalline cellulose, 2.5-3.5 parts by weight of croscarmellose sodium, and 0.6-0.9 part by weight of magnesium stearate.

An apremilast tablet according to the first aspect of the invention, wherein the apremilast is apremilast form a, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at about the following 2-theta angles: 8.1 plus or minus 0.1, 14.4 plus or minus 0.1, 15.2 plus or minus 0.1, 17.4 plus or minus 0.1, 18.4 plus or minus 0.1, 19.2 plus or minus 0.1, 20.5 plus or minus 0.1, 22.8 plus or minus 0.1, 23.2 plus or minus 0.1, 23.6 plus or minus 0.1, 24.5 plus or minus 0.1 and 25.1 plus or minus 0.1.

An apremilast tablet according to the first aspect of the invention, wherein the apremilast is apremilast form B, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 10.1 plus or minus 0.1, 12.4 plus or minus 0.1, 13.5 plus or minus 0.1, 15.7 plus or minus 0.1, 16.3 plus or minus 0.1, 18.1 plus or minus 0.1, 20.7 plus or minus 0.1, 22.5 plus or minus 0.1, 24.7 plus or minus 0.1, 26.2 plus or minus 0.1, 26.9 plus or minus 0.1 and 29.1 plus or minus 0.1.

An apremilast tablet according to the first aspect of the invention, wherein the apremilast is apremilast form C, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.5 +/-0.1, 11.3 +/-0.1, 15.3 +/-0.1, 16.4 +/-0.1, 17.8 +/-0.1, 21.4 +/-0.1, 22.6 +/-0.1, 23.5 +/-0.1, 24.8 +/-0.1, 25.5 +/-0.1, 26.4 +/-0.1 and 27.6 +/-0.1.

An apremilast tablet according to the first aspect of the invention, wherein the apremilast is apremilast form D, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.5 +/-0.1, 9.6 +/-0.1, 11.3 +/-0.1, 13.9 +/-0.1, 16.3 +/-0.1, 17.7 +/-0.1, 20.5 +/-0.1, 23.2 +/-0.1, 24.6 +/-0.1, 25.2 +/-0.1, 26.0 +/-0.1 and 28.8 +/-0.1.

An apremilast tablet according to the first aspect of the invention, wherein the apremilast is apremilast form E, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.6 +/-0.1, 9.2 +/-0.1, 11.4 +/-0.1, 15.5 +/-0.1, 16.5 +/-0.1, 17.9 +/-0.1, 19.6 +/-0.1, 20.5 +/-0.1, 21.6 +/-0.1, 22.8 +/-0.1, 23.8 +/-0.1 and 26.6 +/-0.1.

An apremilast tablet according to the first aspect of the invention, wherein the apremilast is apremilast form F, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 8.1 plus or minus 0.1, 8.6 plus or minus 0.1, 15.6 plus or minus 0.1, 17.3 plus or minus 0.1, 19.3 plus or minus 0.1, 21.4 plus or minus 0.1, 22.8 plus or minus 0.1, 24.6 plus or minus 0.1, 25.4 plus or minus 0.1, 25.9 plus or minus 0.1, 26.6 plus or minus 0.1 and 27.7 plus or minus 0.1.

An apremilast tablet according to the first aspect of the invention, wherein the apremilast is apremilast form G, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.9 plus or minus 0.1, 9.5 plus or minus 0.1, 11.7 plus or minus 0.1, 15.7 plus or minus 0.1, 16.8 plus or minus 0.1, 18.1 plus or minus 0.1, 19.7 plus or minus 0.1, 21.8 plus or minus 0.1, 22.8 plus or minus 0.1, 25.1 plus or minus 0.1, 25.8 plus or minus 0.1 and 26.7 plus or minus 0.1.

The crystals of apremilast a-G described above are readily available, including commercially available or literature-referenced methods. For example, apremilast form B can be obtained from a variety of solvents, including, but not limited to, solvent systems comprising 2-propanol, acetone, acetonitrile, ethanol, ethyl acetate, heptane, methanol, methyl ethyl ketone, methyl tert-butyl ether, dichloromethane, n-butanol, n-butyl acetate, tetrahydrofuran, toluene, water, and mixtures comprising two or more. Form B may be obtained by crystallization from a system comprising a 1:1 ethanol-water solvent, for example, by a process comprising evaporating a 1:1 ethanol-water solvent system at about 25 ℃ and then isolating form B. For example, form B can be obtained by crystallization from a 1:1 acetone-ethanol solvent system; for example, a process by slurrying an apremilast solid in a 1:1 ethanol-water solvent at about 25 ℃ for about 2 days, followed by isolation of form B.

An apremilast tablet according to the first aspect of the invention, wherein the surface of the tablet is further coated with a coating agent.

The apremilast tablet according to the first aspect of the invention, wherein the weight of the coating layer is 2 to 10%, in particular 3 to 6%, such as 3 to 5%, such as 4% of the weight of the core tablet (also called plain tablet).

The apremilast tablet according to the first aspect of the invention, wherein the coating agent is a film coating material. Film coating film-forming materials are well known to those skilled in the art. Exemplary film coating film forming materials are, for example, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, and the like, and combinations thereof.

An apremilast tablet according to the first aspect of the invention, wherein the film coating material further comprises one or more of the following: talc, titanium dioxide, colorants, and the like.

An apremilast tablet according to the first aspect of the invention, wherein the colorant in the film coating material is such as, but not limited to, one or more of the following: ferric oxide, yellow ferric oxide, carmine, caramel, beta-carotene, sodium riboflavin phosphate, aluminum lakes, and the like, and combinations thereof.

The apremilast tablet according to the first aspect of the invention, wherein the coating agent is

For example, is

II, e.g. are

II85F94245、

II85F165037、

II85F1424 and the like.

The apremilast tablet according to the first aspect of the present invention contains the active ingredient apremilast in an amount of 5 to 50mg per tablet, for example, 10 to 30mg per tablet. For example, it contains the active ingredient apremilast in an amount of 10mg, 20mg, 30mg per tablet.

An apremilast tablet according to the first aspect of the invention, which is prepared by a process comprising the steps of:

(i) uniformly mixing apremilast, lactose, microcrystalline cellulose and croscarmellose sodium according to the formula amount of 1/3-2/3, and preparing granules by a dry method by using a compression roller device;

(ii) (ii) adding the balance of croscarmellose sodium into the granules obtained in step (i), uniformly mixing, and then adding magnesium stearate and uniformly mixing;

(iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets; optionally (c) is

(iv) Coating the obtained plain tablet with coating solution to obtain coated tablet.

An apremilast tablet according to the first aspect of the invention, further comprising a phospholipid (e.g. soya lecithin or egg lecithin) and dibasic calcium phosphate (e.g. anhydrous dibasic calcium phosphate).

The apremilast tablet according to the first aspect of the present invention, the amount of the phospholipid is 1 to 2 parts by weight and the amount of the calcium hydrogen phosphate is 6 to 8 parts by weight, based on 10 parts by weight of apremilast.

An apremilast tablet according to the first aspect of the invention, wherein the phospholipid and dibasic calcium phosphate are added by the process of step (ia): and (ia) spraying the Apremilast fine powder into a phospholipid ethanol solution (for example, the concentration of phospholipid in ethanol is 15-20%) under a fluidized state, adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain the pre-treated Apremilast particles. The pre-treated granules are then used in step (i) of the present invention to prepare plain tablets by mixing with lactose, microcrystalline cellulose and the like. It has been found in the present invention that the mixing of lactose with apremilast results in a modification of the apremilast crystal profile, and it has been surprisingly found that the problem of lactose resulting in a modification of the apremilast crystal profile can be overcome by the above-described pretreatment of apremilast with phospholipids and dibasic calcium phosphate. It was also found that the phenomenon of lactose causing a modification of the apremilast crystal profile appears to be related to a humid environment.

Further, the second aspect of the present invention provides a process for preparing an apremilast tablet comprising the following components:

10 parts by weight of apremilast, 45-65 parts by weight of lactose (such as an anhydride or monohydrate thereof), 15-30 parts by weight of microcrystalline cellulose, 2-4 parts by weight of croscarmellose sodium, and 0.5-1 part by weight of magnesium stearate;

the method comprises the following steps:

(iii) (iii) tabletting the mixed granules obtained in step (ii) on a tabletting machine to obtain tablet cores; optionally (c) is

(iv) The resulting tablet cores are coated with a coating solution.

The method according to the second aspect of the invention, wherein the apremilast tablet comprises the following components: 10 parts by weight of apremilast, 50-65 parts by weight of lactose (such as an anhydride or monohydrate thereof), 20-30 parts by weight of microcrystalline cellulose, 2-4 parts by weight of croscarmellose sodium, and 0.5-1 part by weight of magnesium stearate.

The method according to the second aspect of the invention, wherein the apremilast tablet comprises the following components: 10 parts by weight of apremilast, 55-62 parts by weight of lactose (such as an anhydrate or monohydrate thereof), 22-28 parts by weight of microcrystalline cellulose, 2.5-3.5 parts by weight of croscarmellose sodium, and 0.6-0.9 part by weight of magnesium stearate.

The method according to the second aspect of the present invention, wherein the apremilast is apremilast form a, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 8.1 plus or minus 0.1, 14.4 plus or minus 0.1, 15.2 plus or minus 0.1, 17.4 plus or minus 0.1, 18.4 plus or minus 0.1, 19.2 plus or minus 0.1, 20.5 plus or minus 0.1, 22.8 plus or minus 0.1, 23.2 plus or minus 0.1, 23.6 plus or minus 0.1, 24.5 plus or minus 0.1 and 25.1 plus or minus 0.1.

The method according to the second aspect of the present invention, wherein the apremilast is apremilast form B, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 10.1 plus or minus 0.1, 12.4 plus or minus 0.1, 13.5 plus or minus 0.1, 15.7 plus or minus 0.1, 16.3 plus or minus 0.1, 18.1 plus or minus 0.1, 20.7 plus or minus 0.1, 22.5 plus or minus 0.1, 24.7 plus or minus 0.1, 26.2 plus or minus 0.1, 26.9 plus or minus 0.1 and 29.1 plus or minus 0.1.

The method according to the second aspect of the present invention, wherein the apremilast is apremilast form C, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.5 +/-0.1, 11.3 +/-0.1, 15.3 +/-0.1, 16.4 +/-0.1, 17.8 +/-0.1, 21.4 +/-0.1, 22.6 +/-0.1, 23.5 +/-0.1, 24.8 +/-0.1, 25.5 +/-0.1, 26.4 +/-0.1 and 27.6 +/-0.1.

The method according to the second aspect of the present invention, wherein the apremilast is apremilast form D, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.5 +/-0.1, 9.6 +/-0.1, 11.3 +/-0.1, 13.9 +/-0.1, 16.3 +/-0.1, 17.7 +/-0.1, 20.5 +/-0.1, 23.2 +/-0.1, 24.6 +/-0.1, 25.2 +/-0.1, 26.0 +/-0.1 and 28.8 +/-0.1.

The method according to the second aspect of the present invention, wherein the apremilast is apremilast form E, which comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum, as analyzed by X-ray powder diffraction: 7.6 +/-0.1, 9.2 +/-0.1, 11.4 +/-0.1, 15.5 +/-0.1, 16.5 +/-0.1, 17.9 +/-0.1, 19.6 +/-0.1, 20.5 +/-0.1, 21.6 +/-0.1, 22.8 +/-0.1, 23.8 +/-0.1 and 26.6 +/-0.1.

The method according to the second aspect of the present invention, wherein the apremilast is apremilast form F, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 8.1 plus or minus 0.1, 8.6 plus or minus 0.1, 15.6 plus or minus 0.1, 17.3 plus or minus 0.1, 19.3 plus or minus 0.1, 21.4 plus or minus 0.1, 22.8 plus or minus 0.1, 24.6 plus or minus 0.1, 25.4 plus or minus 0.1, 25.9 plus or minus 0.1, 26.6 plus or minus 0.1 and 27.7 plus or minus 0.1.

The method according to the second aspect of the present invention, wherein the apremilast is apremilast form G, which comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum, as analyzed by X-ray powder diffraction: 7.9 plus or minus 0.1, 9.5 plus or minus 0.1, 11.7 plus or minus 0.1, 15.7 plus or minus 0.1, 16.8 plus or minus 0.1, 18.1 plus or minus 0.1, 19.7 plus or minus 0.1, 21.8 plus or minus 0.1, 22.8 plus or minus 0.1, 25.1 plus or minus 0.1, 25.8 plus or minus 0.1 and 26.7 plus or minus 0.1.

The process according to the second aspect of the present invention, wherein the surface of the tablet is further coated with a coating agent.

The process according to the second aspect of the invention, wherein the weight of the coating layer is 2 to 10%, in particular 3 to 6%, such as 3 to 5%, such as 4% of the weight of the tablet core (also called plain tablet).

The method according to the second aspect of the present invention, wherein the coating agent is a film coating material. Film coating film-forming materials are well known to those skilled in the art. Exemplary film coating film forming materials are, for example, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, and the like, and combinations thereof.

The method according to the second aspect of the present invention, wherein the film coating material further comprises one or more of the following: talc, titanium dioxide, colorants, and the like, and combinations thereof.

The method according to the second aspect of the present invention, wherein the colorant in the film coat material is for example, but not limited to, one or more of the following: ferric oxide, yellow ferric oxide, carmine, caramel, beta-carotene, sodium riboflavin phosphate, aluminum lakes, and the like, as well as combinations thereof.

The method according to the second aspect of the present invention, wherein the coating agent is

For example, is

II, e.g. are

II85F94245、

II85F 165037、

II85F1424 and the like.

The method according to the second aspect of the present invention, wherein the amount of the active ingredient apremilast contained in each tablet of the apremilast tablet is 5 to 50mg, for example, the amount of the active ingredient apremilast contained in each tablet is 10 to 30 mg. For example, it contains the active ingredient apremilast in an amount of 10mg, 20mg, 30mg per tablet.

The method according to the second aspect of the present invention, wherein the apremilast tablet further comprises a phospholipid (e.g. soy lecithin or egg yolk lecithin) and dibasic calcium phosphate (e.g. anhydrous dibasic calcium phosphate).

The method according to the second aspect of the present invention, wherein the apremilast tablet has a phospholipid amount of 1 to 2 parts by weight and a calcium hydrogen phosphate amount of 6 to 8 parts by weight, based on 10 parts by weight of apremilast.

The method according to the second aspect of the present invention, wherein the phospholipid and calcium hydrogen phosphate are added by the method of the following step (ia): and (ia) spraying the Apremilast fine powder into a phospholipid ethanol solution (for example, the concentration of phospholipid in ethanol is 15-20%) under a fluidized state, adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain the pre-treated Apremilast particles. The pre-treated granules are then used in step (i) of the present invention to prepare plain tablets by mixing with lactose, microcrystalline cellulose and the like.

Further, in a third aspect, the invention provides a composition comprising the following components in the preparation of a medicament for treating an adult patient with active psoriatic arthritis, an adult patient with moderate to severe plaque psoriasis who is suitable for phototherapy or systemic therapy, and behcet's disease: (

Disease) in adult patients with oral ulcers: 10 parts by weight of apremilast, 45-65 parts by weight of lactose (such as an anhydride or monohydrate thereof), 15-30 parts by weight of microcrystalline cellulose, 2-4 parts by weight of croscarmellose sodium, and 0.5-1 part by weight of magnesium stearate.

The use according to the third aspect of the invention, wherein the composition comprises the following components: 10 parts by weight of apremilast, 50-65 parts by weight of lactose (such as an anhydride or monohydrate thereof), 20-30 parts by weight of microcrystalline cellulose, 2-4 parts by weight of croscarmellose sodium, and 0.5-1 part by weight of magnesium stearate.

The use according to the third aspect of the invention, wherein the composition comprises the following components: 10 parts by weight of apremilast, 55-62 parts by weight of lactose (such as an anhydrate or monohydrate thereof), 22-28 parts by weight of microcrystalline cellulose, 2.5-3.5 parts by weight of croscarmellose sodium, and 0.6-0.9 part by weight of magnesium stearate.

Use according to the third aspect of the invention, wherein the apremilast is apremilast form a, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at angles of about 2 Θ as follows: 8.1 plus or minus 0.1, 14.4 plus or minus 0.1, 15.2 plus or minus 0.1, 17.4 plus or minus 0.1, 18.4 plus or minus 0.1, 19.2 plus or minus 0.1, 20.5 plus or minus 0.1, 22.8 plus or minus 0.1, 23.2 plus or minus 0.1, 23.6 plus or minus 0.1, 24.5 plus or minus 0.1 and 25.1 plus or minus 0.1.

Use according to the third aspect of the invention, wherein the apremilast is apremilast form B, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at angles of about 2 Θ as follows: 10.1 plus or minus 0.1, 12.4 plus or minus 0.1, 13.5 plus or minus 0.1, 15.7 plus or minus 0.1, 16.3 plus or minus 0.1, 18.1 plus or minus 0.1, 20.7 plus or minus 0.1, 22.5 plus or minus 0.1, 24.7 plus or minus 0.1, 26.2 plus or minus 0.1, 26.9 plus or minus 0.1 and 29.1 plus or minus 0.1.

Use according to the third aspect of the invention, wherein the apremilast is apremilast form C, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at angles of about 2 Θ as follows: 7.5 +/-0.1, 11.3 +/-0.1, 15.3 +/-0.1, 16.4 +/-0.1, 17.8 +/-0.1, 21.4 +/-0.1, 22.6 +/-0.1, 23.5 +/-0.1, 24.8 +/-0.1, 25.5 +/-0.1, 26.4 +/-0.1 and 27.6 +/-0.1.

Use according to the third aspect of the invention, wherein the apremilast is apremilast form D, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at angles of about 2 Θ as follows: 7.5 +/-0.1, 9.6 +/-0.1, 11.3 +/-0.1, 13.9 +/-0.1, 16.3 +/-0.1, 17.7 +/-0.1, 20.5 +/-0.1, 23.2 +/-0.1, 24.6 +/-0.1, 25.2 +/-0.1, 26.0 +/-0.1 and 28.8 +/-0.1.

Use according to the third aspect of the invention, wherein the apremilast is apremilast form E, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at angles of about 2 Θ as follows: 7.6 +/-0.1, 9.2 +/-0.1, 11.4 +/-0.1, 15.5 +/-0.1, 16.5 +/-0.1, 17.9 +/-0.1, 19.6 +/-0.1, 20.5 +/-0.1, 21.6 +/-0.1, 22.8 +/-0.1, 23.8 +/-0.1 and 26.6 +/-0.1.

Use according to the third aspect of the invention, wherein the apremilast is apremilast form F, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at angles of about 2 Θ as follows: 8.1 plus or minus 0.1, 8.6 plus or minus 0.1, 15.6 plus or minus 0.1, 17.3 plus or minus 0.1, 19.3 plus or minus 0.1, 21.4 plus or minus 0.1, 22.8 plus or minus 0.1, 24.6 plus or minus 0.1, 25.4 plus or minus 0.1, 25.9 plus or minus 0.1, 26.6 plus or minus 0.1 and 27.7 plus or minus 0.1.

Use according to the third aspect of the invention, wherein the apremilast is apremilast form G, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks in the XRD spectrum at angles of about 2 Θ as follows: 7.9 plus or minus 0.1, 9.5 plus or minus 0.1, 11.7 plus or minus 0.1, 15.7 plus or minus 0.1, 16.8 plus or minus 0.1, 18.1 plus or minus 0.1, 19.7 plus or minus 0.1, 21.8 plus or minus 0.1, 22.8 plus or minus 0.1, 25.1 plus or minus 0.1, 25.8 plus or minus 0.1 and 26.7 plus or minus 0.1.

The use according to the third aspect of the invention, wherein the medicament is a medicament in the form of a tablet.

The use according to the third aspect of the present invention, wherein the surface of the tablet is further coated with a coating agent.

The use according to the third aspect of the invention, wherein the weight of the coating layer is 2-10%, in particular 3-6%, such as 3-5%, such as 4% of the weight of the tablet core (also known as plain tablet).

The use according to the third aspect of the invention, wherein the coating agent is a film coating material. Film coating film-forming materials are well known to those skilled in the art. Exemplary film coating film forming materials are, for example, but not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, and the like, and combinations thereof.

The use according to the third aspect of the invention, wherein the film coating material further comprises one or more of the following: talc, titanium dioxide, colorants, and the like, and combinations thereof.

Use according to the third aspect of the invention, wherein the colorant in the film coat material is for example, but not limited to, one or more of the following: ferric oxide, yellow ferric oxide, carmine, caramel, beta-carotene, sodium riboflavin phosphate, aluminum lakes, and the like, and combinations thereof.

The use according to the third aspect of the invention, wherein said coating agent is

For example, is

II, e.g. are

II85F94245、

II85F 165037、

II85F1424 and the like.

The use according to the third aspect of the present invention, wherein the tablet contains the active ingredient apremilast in an amount of 5 to 50mg per tablet, for example, 10 to 30mg per tablet. For example, it contains the active ingredient apremilast in an amount of 10mg, 20mg, 30mg per tablet.

The use according to the third aspect of the present invention, wherein the tablet is prepared by a method comprising the steps of:

The use according to the third aspect of the invention, wherein the tablet further comprises a phospholipid (e.g. soya lecithin or egg yolk lecithin) and dibasic calcium phosphate (e.g. anhydrous dibasic calcium phosphate).

The use according to the third aspect of the present invention, wherein the amount of the phospholipid in the tablet is 1 to 2 parts by weight and the amount of the calcium hydrogen phosphate is 6 to 8 parts by weight based on 10 parts by weight of apremilast.

The use according to the third aspect of the present invention, wherein the phospholipid and calcium hydrogen phosphate in the tablet are added by the method of the following step (ia): and (ia) spraying the Apremilast fine powder into a phospholipid ethanol solution (for example, the concentration of phospholipid in ethanol is 15-20%) under a fluidized state, adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain the pre-treated Apremilast particles. The pre-treated granules are then used in step (i) of the present invention to prepare plain tablets by mixing with lactose, microcrystalline cellulose and the like. In the present invention, the term "fine powder" used to describe the solid material means a powder capable of passing through a 100-mesh sieve, unless otherwise specified.

In the steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, the above-described method steps can be fully summarized by those skilled in the art in light of the detailed disclosure throughout the present disclosure.

Any embodiment of any aspect of the invention may be combined with any other embodiment of the invention, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in any other embodiment of the invention, provided that they do not contradict.

The invention is further described below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

Apremilast (APR) is a novel oral, small molecule phosphodiesterase 4(PDE4) inhibitor. Apremilast can inhibit PDE4 activity, increase intracellular cyclic adenosine monophosphate level, further regulate expression of tumor necrosis factor and other inflammatory cytokines, and finally inhibit inflammatory reaction. The composition can be used for treating adult patients with active psoriatic arthritis, adult patients with moderate to severe plaque psoriasis who are suitable for phototherapy or systemic therapy, and Behcet's disease

Disease) associated adult patients with oral ulcers.

Apremilast is a PDE4 inhibitor, specific for cyclic adenosine monophosphate (cAMP). PDE4 plays an important role in the hydrolysis of cAMP, and inhibition of PDE4 results in increased intracellular cAMP levels, which can suppress immune and inflammatory responses. The product is effective by regulating the amount of proinflammatory and anti-inflammatory factors in cells. The product can inhibit TNF-alpha release from human synovial cells in a dose-dependent manner, and has obvious inhibition effect on experimental arthritis. In vitro experiment the product can inhibit peripheral monocyte from producing chemokines CXCL9 and CXCL10, gamma-interferon, tumor necrosis factor alpha, IL-2, IL-12 and IL-23. The production of tumor necrosis factor alpha by natural killer cells and keratinocytes is also inhibited.

Psoriasis is considered to be a Th 1-mediated autoimmune skin disease because of the involvement of the pro-inflammatory cytokines IFN-gamma, TNF-alpha. Apremilast is a small molecule phosphodiesterase 4(PDE4) inhibitor, with a semi-inhibitory concentration (IC50) of 74nmol/L inhibiting PDE-4 isolated from human monocytes U937, PDE4 being a cyclic adenosine monophosphate (cAMP) specific PDE, cAMP monophosphate being a key second messenger that regulates inflammatory responses, helps to maintain homeostasis by regulating the network of pro-and anti-inflammatory mediators, cAMP is regulated by intracellular Phosphodiesterases (PDEs), being the only way to degrade cAMP to AMP, thus increasing pro-inflammatory mediator production and decreasing anti-inflammatory mediator production. PDEs constitute at least 11 enzyme families based on amino acid sequence homology, sensitivity to inhibitors, and biochemical properties. Each enzyme within the PDE4 family targets its degraded cAMP and constitutes 4 subtypes (PDE4A through PDE4D) which are localized in the brain and in immunocompetent cells such as neutrophils, T lymphocytes, macrophages and eosinophils. Within this group, the PDE4 family (4-gene enzyme) plays a key role in degrading cAMP in inflammatory cells as well as endothelial cells, smooth muscle cells and keratinocytes.

Pharmacokinetic aspects of apremilast. Absorption: after oral administration of apremilast, the peak time to peak plasma concentration (Tmax) is 2.5h, t1/2 is 5-7 h, and the average oral bioavailability is 70%. Distribution: the binding rate of apremilast to protein in human plasma was about 68%. The mean apparent volume (Vd) was 87L. Metabolism: after oral administration, apremilast is the major circulating component (45%), followed by the inactive metabolite M12 of glucuronide binding to o-methylated apremilast (39%). It is widely metabolized in humans, with up to 23 metabolites found in plasma, urine and feces. Apremilast is a product of the combined action of Cytochrome (CYP) oxidative metabolism and subsequent glycolysis and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is mediated primarily by CYP3a4, with minor contributions from CYP1a2 and CYP2a 6. Eliminating: in healthy subjects, apremilast has a plasma clearance of about 10L/hr and a final elimination half-life of about 6-9 hours. After oral administration of radiolabeled april powder, approximately 58% and 39% of the radioactivity was recovered in urine and feces, respectively, and approximately 3% and 7% of the radioactive dose was recovered in urine and feces, respectively.

For clinical trials in psoriatic arthritis patients. The safety and efficacy of the product was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies (study PSA-1, PSA-2, PSA-3). A total of 1493 adult PSA patients were enrolled in the study, with the patients diagnosed with PSA for at least 6 months. Of the 3 trials, patients received randomized placebo (n-496), 20mg (n-500) or 30mg (n-497), bid. Patients can continue to take DMARDs (methotrexate, sulfasalazine, leflunomide, small doses of oral corticosteroids, and/or non-steroidal anti-inflammatory drugs (NSAIDs) with the primary endpoint being the percentage of patients who reach the American rheumatic Association (ACR)20 response at week 16. in 3 studies, patients who took this product had a significantly higher proportion of ACR20 response patients at week 16 than placebo, study PSA-1 had 30mg of this product, study bid + DMARD had 38%, placebo + DMARDs had 19%, study PSA-2 had 32%, placebo had 19%, study PSA-3 had 41%, and placebo had 18%, study PSA-1 had taken this product at 30mg, bid had a significantly higher improvement in physical and physical symptoms, function, and other characteristic manifestations of psoriatic arthritis at week 16 than placebo, including joint swelling and tenderness, Skin and quality of life; the health assessment questionnaire disability index (HAQ-DI) score was also much improved compared to placebo, with a proportion of HAQ-DI responders of 38% in this group and 27% in the placebo group. This is consistent with the results observed in PSA-2 and PSA-3. The results of the three studies show that the product is effective in treating PSA and has adverse reaction within an acceptable range.

For clinical trials in plaque psoriasis patients. The effectiveness and safety of the product in treating plaque psoriasis is evaluated in a multicenter, randomized, placebo-controlled clinical trial at phase IIb. Plaque psoriasis patients older than 18 years receive this product at random at 1:1 in 10mg (n-89), 20mg (n-87), 30mg (n-88) or placebo (n-88). For 16 weeks of treatment, the proportion of patients with at least a 75% reduction in psoriasis area and severity index (PASI-75) from baseline was 5 (6%), 10 (11%) in the 10mg group, 25 (29%) in the 20mg group, 36 (41%) in the 30mg group, no significant difference between the 10mg group and the placebo group, and statistical significance was observed for the differences between the 20mg group, the 30mg group and the placebo group. The vast majority of adverse events (96%) were mild to moderate, including nausea, diarrhea, headache, gastroenteritis, or dyspepsia. The test shows that the product is safe and effective for treating plaque psoriasis and has good tolerance.

Compared with biological preparations such as secukinumab, simetrol, enril and the like or other traditional treatment medicines for treating psoriasis and psoriatic arthritis, the apremilast has the obvious advantages that:

good selectivity and wide application. As selective inhibitors of phosphodiesterase-4 (PDE-4), are effective against both psoriasis and arthropathic psoriasis, including in a population of patients previously treated with biologies or conventional systemic medications.

The oral administration is convenient. As a small molecular compound, the compound is orally taken, is convenient to carry, is convenient for patients to take, avoids adverse reactions such as skin irritation caused by injection administration, and does not need to frequently monitor laboratory indexes.

Single administration and definite curative effect. The single administration is adopted, the curative effect is not inferior to that of biological preparations such as secukinumab, adalimumab (cefetamet), etanercept (enrichine), infliximab and the like, and the traditional treatment medicine is obviously superior.

Low recurrence rate and good safety. Clinical data show that the severity of nail, scalp and palmoplantar (hand and foot) psoriasis obtained at 16 weeks of treatment is significantly improved and maintained for the whole 52 weeks, so that the patient's condition is significantly and persistently improved with clinical significance.

Short half-life and high tolerance. Apremilast has a short half-life and a high safety factor for discontinuing treatment if necessary. Therefore, apremilast can be applied to patients with plaque psoriasis and joint psoriasis who are not treated or contraindicated by traditional systemic medications, and patients with poor curative effect or poor compliance of biological agents.

The usage and amounts of apremilast are generally as follows: to reduce gastrointestinal symptoms, the recommended dose of 30mg was adjusted 2 times daily by instillation according to the following dosing schedule: day 1, morning 10 mg; day 2, morning 10mg and evening 10 mg; day 3, 10mg in the morning and 20mg in the evening; day 4, morning 20mg and evening 20 mg; day 5, 20mg in the morning and 30mg in the evening; on day 6 and thereafter, 30mg was administered 2 times a day. It can be taken with or without food, and is not pulverized, cracked or chewed.

Using the process of the present invention, the tablets exhibit one or more of the advantageous properties as described herein.

Drawings

FIG. 1 is a powder X-ray diffraction pattern of an apremilast drug substance used in the present invention.

FIG. 2 is a powder X-ray diffraction pattern of different materials measured and compared.

Detailed Description

The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it.

In the following tests, the proportions by weight of the various materials per tablet are indicated, but in the actual preparation of the tablets, at least 200g of apremilast are dosed. In the following experiments, various materials used for preparing tablets were previously pulverized into fine powders that can pass through a 100-mesh sieve, unless otherwise specified, but it is needless to say that the phospholipid added in the form of a liquid is not limited thereto and is not necessarily previously pulverized. In the following specific examples of preparing tablets, the tablets were compressed at a dose containing 10mg of apremilast per tablet, as not specifically mentioned. The dibasic calcium phosphate used in the examples herein is anhydrous dibasic calcium phosphate, unless otherwise specified. In the following experiments, unless otherwise specified, the apremilast drug substance used was its B form, which was analyzed by X-ray powder diffraction and included diffraction peaks at the following 2 θ angles in the XRD spectrum: 10.1 plus or minus 0.1, 12.4 plus or minus 0.1, 13.5 plus or minus 0.1, 15.7 plus or minus 0.1, 16.3 plus or minus 0.1, 18.1 plus or minus 0.1, 20.7 plus or minus 0.1, 22.5 plus or minus 0.1, 24.7 plus or minus 0.1, 26.2 plus or minus 0.1, 26.9 plus or minus 0.1 and 29.1 plus or minus 0.1.

Preparation example 1 preparation of plain tablets of Apremilast

Prescription:

10 parts by weight of apremilast,

60 parts by weight of lactose monohydrate,

26.25 parts by weight of microcrystalline cellulose,

3 portions of croscarmellose sodium (internal addition: 2: 1),

0.75 part by weight of magnesium stearate.

The preparation method comprises the following steps:

(i) uniformly mixing apremilast, lactose, microcrystalline cellulose and croscarmellose sodium, and preparing granules by a dry method by using a compression roller device;

(iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets.

The term "internal addition" is added to the tablet prior to granulation to prepare the tablet, i.e., the portion of croscarmellose sodium added in step (i) above; and the term "additional" is added after granulation to make the tablet, i.e., the portion of croscarmellose sodium added in step (ii) above; this is common knowledge in the tablet industry. The dry granulation by the compression roller equipment and the equipment used by the dry granulation are well known in the solid preparation industry, for example, the dry granulation is carried out by a compression roller type dry granulation machine of Beijing Xinlongli scientific and technical company, the feeding speed is 30rpm, the compression roller speed is 10rpm, the oil pressure is 55bar, the rotation speed of a granulator is 110rpm, the aperture of a screen mesh is 1.0mm, and the gap between the compression rollers is 1.0 mm.

Preparation example 2 preparation of plain tablets of Apremilast

Prescription:

10 parts by weight of apremilast,

62 parts by weight of lactose monohydrate,

22 parts by weight of microcrystalline cellulose,

3.5 portions of croscarmellose sodium (internal addition: additional 2: 1),

0.9 part by weight of magnesium stearate.

The preparation method comprises the following steps:

Preparation example 3 preparation of plain tablets of Apremilast

Prescription:

10 parts by weight of apremilast,

55 parts by weight of lactose monohydrate,

28 parts by weight of microcrystalline cellulose,

2.5 parts by weight of croscarmellose sodium (internal addition: additional 2: 1),

0.6 part by weight of magnesium stearate.

The preparation method comprises the following steps:

Preparation example 4 preparation of plain tablets of Apremilast

Prescription:

10 parts by weight of apremilast,

50 parts by weight of lactose monohydrate,

30 parts by weight of microcrystalline cellulose,

4 portions of croscarmellose sodium (added with 1:1) and,

0.5 part by weight of magnesium stearate.

The preparation method comprises the following steps:

Preparation example 5 preparation of plain tablets of Apremilast

Prescription:

10 parts by weight of apremilast,

65 parts by weight of lactose monohydrate,

20 parts by weight of microcrystalline cellulose,

2 portions of croscarmellose sodium (internal addition: 1: 2),

1 part by weight of magnesium stearate.

The preparation method comprises the following steps:

(iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets. In this example, the obtained mixed granules were divided into three portions and each tablet was prepared to have a tablet weight of 10mg, 20mg, and 30mg of apremilast.

Preparation example 6 preparation of Apremilast coated tablet

To be provided with

II85F94245 (Callerkang corporation) film coating premix, the coating weight of the tablet with the specification of 10 mg/tablet obtained in the preparation examples 1-5 is increased by 4 percent; to be provided with

II85F165037 (Calekang Co.) film coating premix for 20 mg/tablet size tablet obtained in preparation example 5, the coating weight is increased by 5%; to be provided with

II85F17424 (Callerkang Corp.) film coating premix tablets of 30 mg/tablet size obtained in preparation example 5 were coated with a 3% weight gain. Coating parameter referencing

The technical instructions of (1).

Preparation example 11 preparation of plain tablets of Apremilast

Referring to the formulation and preparation of preparation example 1, but with apremilast added after having been treated with 1.5 parts by weight of phospholipids and 7 parts by weight of dibasic calcium phosphate by the following procedure (ia), the complete tablet is prepared as follows: (ia) spraying the Apremilast fine powder in a fluidized state, adding a phospholipid ethanol solution (the phospholipid is prepared into a solution with the concentration of 18 percent by ethanol), adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain pre-treated Apremilast particles; (i) uniformly mixing the pretreated apremilast granules, lactose, microcrystalline cellulose and croscarmellose sodium, and preparing the granules by a dry method by using a compression roller device; (ii) (ii) adding the balance of croscarmellose sodium into the granules obtained in step (i), uniformly mixing, and then adding magnesium stearate and uniformly mixing; (iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets. In a specific embodiment of the invention, the phospholipid used is soybean phospholipid, as not otherwise specified.

Preparation example 12 preparation of plain tablets of Apremilast

Referring to the formulation and preparation of preparation example 4, but with apremilast added after having been treated with 1 part by weight of phospholipid and 8 parts by weight of dibasic calcium phosphate by the following procedure (ia), the complete tablet is prepared as follows: (ia) spraying the Apremilast fine powder in a fluidized state, adding a phospholipid ethanol solution (the phospholipid is prepared into a solution with the concentration of 15% by ethanol), adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain pre-treated Apremilast particles; (i) uniformly mixing the pretreated apremilast granules, lactose, microcrystalline cellulose and croscarmellose sodium, and preparing the granules by a dry method by using a compression roller device; (ii) (ii) adding the balance of croscarmellose sodium into the granules obtained in step (i), uniformly mixing, and then adding magnesium stearate and uniformly mixing; (iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets.

Preparation example 13 preparation of plain tablets of Apremilast

Referring to the formulation and preparation of preparation example 5, but with apremilast added after having been treated with 2 parts by weight of phospholipid and 6 parts by weight of dibasic calcium phosphate by the following procedure (ia), the complete tablet is prepared as follows: (ia) spraying the Apremilast fine powder in a fluidized state, adding a phospholipid ethanol solution (the phospholipid is prepared into a solution with the concentration of 20% by ethanol), adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain pre-treated Apremilast particles; (i) uniformly mixing the pretreated apremilast granules, lactose, microcrystalline cellulose and croscarmellose sodium, and preparing the granules by a dry method by using a compression roller device; (ii) (ii) adding the balance of croscarmellose sodium into the granules obtained in step (i), uniformly mixing, and then adding magnesium stearate and uniformly mixing; (iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets (each tablet containing 10mg of apremilast).

Preparation example 14 preparation of plain tablets of Apremilast

Referring to the formulation and preparation of preparation example 2, but with apremilast added after having been treated with 1.2 parts by weight of phospholipids and 7.5 parts by weight of dibasic calcium phosphate by the following procedure (ia), the complete tablet is prepared as follows: (ia) spraying the Apremilast fine powder in a fluidized state, adding a phospholipid ethanol solution (the phospholipid is prepared into a solution with the concentration of 20% by ethanol), adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain pre-treated Apremilast particles; (i) uniformly mixing the pretreated apremilast granules, lactose, microcrystalline cellulose and croscarmellose sodium, and preparing the granules by a dry method by using a compression roller device; (ii) (ii) adding the balance of croscarmellose sodium into the granules obtained in step (i), uniformly mixing, and then adding magnesium stearate and uniformly mixing; (iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets (each tablet containing 10mg of apremilast).

Preparation example 15 preparation of plain tablets of Apremilast

Referring to the formulation and preparation of preparation example 3, but with apremilast added after having been treated with 1.8 parts by weight of phospholipids and 6.5 parts by weight of dibasic calcium phosphate by the following procedure (ia), the complete tablet is prepared as follows: (ia) spraying the Apremilast fine powder in a fluidized state, adding a phospholipid ethanol solution (the phospholipid is prepared into a solution with the concentration of 20% by ethanol), adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain pre-treated Apremilast particles; (i) uniformly mixing the pretreated apremilast granules, lactose, microcrystalline cellulose and croscarmellose sodium, and preparing the granules by a dry method by using a compression roller device; (ii) (ii) adding the balance of croscarmellose sodium into the granules obtained in step (i), uniformly mixing, and then adding magnesium stearate and uniformly mixing; (iii) (iii) compressing the mixed granulate obtained in step (ii) on a tabletting machine to obtain tablets in the form of plain tablets (each tablet containing 10mg of apremilast).

Test example 1X-ray powder diffraction analysis of Material

In this test example, the conditions for preparing samples (e.g., powder grinding time, compacted density, etc.) were the same when X-ray powder diffraction analysis was performed on various materials using the following equipment and parameters:

the XRD pattern of the B crystal form apremilast of the bulk drug of the tablet used by the invention is shown in figure 1, and the data of typical diffraction peaks are as follows:

in the above data, the peak Height (Height) had subtracted the background noise. As can be seen from the above data and fig. 1, the form B used herein is consistent with the literature, especially at its typical 2 θ angles of 10.1 ° (which may be referred to as m-peak in the present invention) and 13.5 ° (which may be referred to as n-peak in the present invention), and if m-peak is a main peak and n-peak is a secondary strong peak, both peaks are typical characteristic peaks of form B, under the present measurement apparatus/conditions, the peak height (i.e., peak intensity, counts) of m-peak of apremilast form B bulk drug substance (corresponding to 100% powder material containing apremilast) is 26407, and the peak height of n-peak is 19648.

In addition, XRD patterns of the following materials were tested:

material a is plain tablets obtained according to the formulation and preparation of preparation example 11 but without apremilast (i.e. blank tablets);

material b is a plain tablet obtained according to the formulation and preparation of preparation example 1 but without apremilast (i.e. blank tablet);

material c is the plain tablet obtained in preparation example 11;

the material d is the plain tablet obtained in preparation example 1;

material e is the plain film obtained in preparation example 11 exposed to high humidity;

material f was the plain sheet obtained in preparation example 1 exposed to high humidity.

The high humidity exposure refers to the direct exposure of the tablet to an air environment with 85% relative humidity for 14 days, while other test specimens that have not undergone high humidity exposure are sealed from moist air after manufacture. The XRD patterns of the 6 materials were determined and are summarized in fig. 2. In the graphs, a to f represent XRD curves of 6 materials, respectively, and the m-peak position corresponds to 2 θ being 10.1 °, the n-peak position corresponds to 2 θ being 13.5 °, and the x-peak is located at 2 θ being 9.2 °.

As can be seen from fig. 2: the blank tablets of the material a and the material b without Apremilast are added, and no matter whether phospholipid/calcium hydrophosphate is added or not, diffraction peaks do not exist at m, n and x positions, which shows that the auxiliary materials of the preparation examples 1 and 11 do not interfere with the detection of the m and n peaks at the positions; the two plain sheets of the material c and the material d have diffraction peaks at m and n positions, no diffraction peak at x position, and the m and n peak intensities of the two samples are respectively basically equivalent; the material e plain film has diffraction peaks at m and n and no diffraction peak at x, and the intensities of the m and n peaks are respectively basically equivalent to the curve of the material c; the material f plain sheet has diffraction peaks in both m and n but the intensity is obviously smaller than that of the material d curve, and an obvious diffraction peak appears at x.

The above results show that the two plain films of preparation 1 and preparation 11 have the same diffraction spectrum and present typical Apremilast m and n diffraction peaks at m and n, and no diffraction peak at x; the diffraction spectra of the auxiliary materials (blank tablets) for preparing the two plain tablets are the same and have no diffraction peaks at m, n and x, and the typical diffraction peaks m and n of apremilast still appear in the tablets and are not interfered by the auxiliary materials; the tablets of preparation 11 with the addition of phospholipid/dibasic calcium phosphate still exhibited m and n diffraction peaks of similar intensity to the plain tablets of preparation 11 after being subjected to high humidity exposure, and there was no diffraction peak at x; unfortunately, the tablet of preparation 1 without the addition of phospholipid/dibasic calcium phosphate showed a significant decrease in the intensity of the m and n diffraction peaks after exposure to high humidity compared to the plain tablet of preparation 11, and a typical diffraction peak at x, indicating that apremilast had a change in the crystalline form of the tablet of preparation 1.

In order to quantitatively compare the change in diffraction peak intensity, the peak heights of m, n, and x peaks (characteristic peak intensities) were measured 3 times for each sample, and the peak heights of m, n, and x peaks (counts) of a certain sample were represented by the mean of the 3 measurements. The results for some of the samples are as follows:

test specimen	Pretreatment before testing	The sum of the height of two peaks m + n	Peak height of x
				Crude drug B crystal form apremilast	Direct assay	45832	0
Crude drug B crystal form apremilast	High humidity exposure	46379	0
				Blank tablets of preparation examples 1 to 6	Direct assay	0	0
Blank tablets of preparation examples 1 to 6	High humidity exposure	0	0
				Preparation example 11E13 blank sheet	Direct assay	0	0
Blank tablets of preparation examples 11 to 13	High humidity exposure	0	0
				Preparation examples 1 to 5 plain tablets	Direct assay	4231～4525	0
Preparation examples 1 to 5 plain tablets	High humidity exposure	1834～2021	456～613
				Preparation examples 11 to 13 plain tablets	Direct assay	4152～4383	0
Preparation examples 11 to 13 plain tablets	High humidity exposure	4196～4416	0
				Preparation example 6 coated tablet	Direct assay	4132～4525	0
Preparation example 6 coated tablet	High humidity exposure	4212～4483	0
				Plain tablets of supplementary preparation example 1a	Direct assay	4327～4613	0
Plain tablets of supplementary preparation example 1a	High humidity exposure	4243～4561	0
				Supplement the base tablet of preparation example 11a	Direct assay	4331～4627	0
Supplement the base tablet of preparation example 11a	High humidity exposure	1912～2127	385～537
				Plain tablets of supplementary preparation example 11b	Direct assay	4193～4594	0
Plain tablets of supplementary preparation example 11b	High humidity exposure	1874～2076	406～553

In the table, "direct measurement" means that the powder X-ray diffraction measurement was directly performed on the tablet without subjecting the tablet to a high-humidity exposure treatment.

In the above table, for example, the sum of the m + n peak heights measured directly for the plain sheet in preparation example 1 is 4426, the sum of the m + n peak heights measured directly for the plain sheet in preparation example 1 is 1932, the x peak height is 541, the sum of the m + n peak heights measured directly for the plain sheet in preparation example 11 is 4313, the sum of the m + n peak heights measured directly for the plain sheet in preparation example 11 is 4276, and the preparation example 6 is prepared by mixing the above two kinds of raw materials, and the like

II85F94245 the sum of the m + n peaks measured directly and at high humidity exposure for the coated tablets of preparation 1 was 4312 and 4287, respectively.

The above results show that the peak heights of m and n peaks are reduced by a considerable factor after the bulk drug is diluted by about 10 times with the auxiliary material, while the m and n peak intensities of the tablets of preparation examples 1 to 5 are significantly reduced and an unknown diffraction peak x peak appears after the tablets are exposed to high humidity, and surprisingly, the m and n peak intensities of the tablets added with the phospholipid/calcium hydrophosphate are not changed basically and the unknown diffraction peak x peak is not generated.

In the above table, the base tablet of the supplementary preparation example 1a was prepared as follows: referring to the formula and the preparation method of preparation examples 1-3 respectively, except that lactose is not added (equivalent microcrystalline cellulose is used to replace the weight of the tablet), three kinds of plain tablets are prepared; for example, the sum of the m + n peak heights measured directly and by high humidity exposure of the plain film prepared in preparative example 1a is 4531 and 4478; this indicates that the reason why the m + n two peaks of the sheets of preparation examples 1 to 5 are weakened in strength and the unknown x peak appears after the high-humidity exposure is lactose. That is, tablets containing lactose exhibit a change in the typical diffraction peak of the active drug after exposure to high humidity. However, the above-mentioned change in diffraction peak can be avoided by coating the tablet with a film coat.

In the above table, the base tablet of supplemental preparation example 11a was prepared as follows: referring to the formulas and the preparation methods of preparation examples 11-13 respectively, except that no phospholipid is added, three kinds of plain tablets are prepared; for example, the sum of the m + n peak heights determined directly and by high humidity exposure was 4471 and 1956, respectively, and the x peak height 438, respectively, for the reference preparation example 11a, which was a supplement obtained in preparation example 11; this indicates that the tablets containing lactose had diffraction peaks changed after the high-humidity treatment, although calcium hydrogen phosphate was added.

In the above table, the base tablet of supplemental preparation example 11b was prepared as follows: referring to the formula and the preparation method of preparation examples 11-13 respectively, except that calcium hydrophosphate is not added, three kinds of plain tablets are prepared; for example, the sum of the m + n peak heights determined directly and after high humidity exposure as determined for the supplemental preparation example 11b, reference preparation example 11, is 4286 and 1933, respectively, and the x peak height 447; this indicates that the tablets containing lactose had diffraction peaks changed after the high-humidity treatment, although the phospholipid was further added. The results of the supplementary preparation example 11a and the supplementary preparation example 11b show that only the simultaneous addition of both phospholipid and dibasic calcium phosphate avoids the change in the typical diffraction peak of the active drug after exposure of the lactose-containing tablets to high humidity.

The above results suggest that by adding phospholipid/dibasic calcium phosphate to prepare an apremilast tablet, the tablet can be coated without the need for coating and still have excellent stability. From the production cost, the uncoated tablet is lower in both process time cost and price cost; in addition, since coating is a process of spraying an aqueous coating solution onto the surface of the tablet and drying, this process itself may cause unpredictable effects on the tablet, such as migration of the active ingredient, possible crystal changes of the active ingredient on the tablet surface due to the process of subjecting the active ingredient to the aqueous coating solution, etc., and these effects are difficult to detect/observe. Uncoated tablets are therefore advantageous in some respects over coated tablets.

Test example 2 Performance test of Apremilast sheet

In this test example 2, all of the tablets of preparation examples 1 to 6, which were 10mg size tablets, and preparation examples 11 to 15, which were 10mg size tablets, were subjected to a performance test.

1. Properties of tablet

If the tablet is coated, the coating is removed, and the tablet is spread on paper, and observed with naked eyes to describe its physical properties and state. As a result: all the tablets of the test batches appeared white or off-white, for example the tablet of preparation 11 was a white tablet.

2. Ultraviolet identification of tablets

Taking about 10mg of the fine powder of the tablet agent, placing the fine powder into a 100ml volumetric flask, adding methanol to dissolve and dilute the fine powder to prepare a solution containing about 10 mu g of the fine powder in each 1ml, and placing the solution into an ultraviolet spectrophotometer to scan within the wavelength range of 200-400nm to determine the maximum absorption wavelength. As a result: the tablets of all test batches have absorption maxima at wavelengths of 230, 342nm, for example the tablet of preparation 11 has absorption maxima at wavelengths of 230.2, 341.8 nm. Taking the apremilast raw material as a medicinal methanol solution and diluting the medicinal methanol solution to prepare a solution containing about 10 mu g of apremilast raw material per 1ml, and the determination by the same method also shows that the apremilast raw material has maximum absorption at the wavelengths of 230nm and 342 nm.

3. Determination of the content of active ingredients in tablets

(1) Chromatographic conditions are as follows: the chromatographic column is C18 column, 150mm × 4.6mm, 5 μm; acetonitrile-0.1% formic acid solution (40:60) is used as a mobile phase; the flow rate is 1 ml/min; the detection wavelength was 230nm and the column temperature was 40 ℃. The relative standard deviation of the control solution should not be greater than 1.0%, and the theoretical plate number should not be less than 5000 calculated according to Apremilast peak.

(2) Preparation of a test solution: taking 20 tablets of a batch to be detected, precisely weighing, grinding, taking about 100mg (about equivalent to 10mg of apremilast) of fine powder, precisely weighing, placing in a 100ml volumetric flask, adding about 60ml of mixed solvent (acetonitrile-0.1% formic acid solution 1:1), ultrasonically treating for about 15 minutes, cooling to room temperature, adding the mixed solvent to dilute to a scale, shaking uniformly, filtering, and taking a subsequent filtrate as a sample solution.

(3) Preparation of control solutions: about 20mg of apremilast reference substance was precisely weighed, and placed in a 200ml volumetric flask, and a mixed solvent was added and diluted to prepare a solution containing about 0.1mg of apremilast per 1ml as a reference substance solution.

(4) The determination method comprises the following steps: and (4) sucking 10 mu l of each of the control solution and the test solution, injecting into a liquid chromatograph, and recording the spectrogram.

(5) Calculating formula:

in the formula: v_{To pair}-dilution volume of control; v_{Sample (A)}-the volume of sample dilution; a. the_{To pair}-the main peak area of the control;

A_{sample (A)}-the main peak area of the sample; w_{To pair}-weighing of control, mg; w_{Sample (A)}-weight of test sample, mg.

(6) And (5) judging a result: it is generally required if the tablets contain apremilast (C)₂₂H₂₄N₂O₇S) is 95.0 to 105.0 percent of the marked amount, and the standard is judged to be in accordance with the specification.

(7) Solution stability: the control solution and the test solution were stable within 48 hours at room temperature.

(8) As a result: all test batches of tablets contained apremilast (C)₂₂H₂₄N₂O₇S) are within the range of 98.6-101.2% of the indicated amounts, for example, the content of the tablet of preparation 1 is 99.64%, and the content of the tablet of preparation 11 is 99.82%.

4. Content uniformity of tablets

(1) Chromatographic conditions are as follows: under the same content determination item.

(2) Preparation of a test solution: taking 10 tablets of a batch to be detected, respectively placing the tablets into 10 100ml measuring bottles, adding about 60ml of mixed solvent (acetonitrile-0.1% formic acid solution 1:1), carrying out ultrasonic treatment for about 15 minutes to completely disintegrate the tablets, cooling to room temperature, adding the mixed solvent to dilute to a scale, shaking up, filtering, and taking a subsequent filtrate as a sample solution.

(3) Preparation of control solutions: precisely weighing about 20mg of Apremilast reference substance, placing into a 200ml volumetric flask, adding mixed solvent, ultrasonically dissolving, and diluting to obtain a solution containing about 0.1mg per 1 ml.

(4) The determination method comprises the following steps: respectively injecting 10 μ l of each of the reference solution and the sample solution into a liquid chromatograph, measuring by a content measuring method, and recording the spectrogram.

(5) Calculating formula:

A_{sample (A)}-the main peak area of the sample; w_{To pair}-weight of control, mg.

(6) And (5) judging a result: generally, if A +2.2S is less than or equal to 15.0, the content uniformity of the tablets in a certain batch meets the specification; if A + S>15.0, the regulation is not met; if A +2.2S>15.0, and A + S is less than or equal to 15.0, 20 additional retests should be taken. Calculating the average value of 30 pieces (pieces) according to the results of the initial and secondary tests

The standard deviation S and the absolute value A of the difference between the marked quantity and the mean, if A²+S²Is less than or equal to 56.25(A is less than or equal to 3.75) or A +1.7S is less than or equal to 15.0(A is more than or equal to 3.75), and meets the regulation.

(7) As a result: the A +2.2S value of the tablets of all test batches is less than 15.0 and is within the range of 2.2-5.8, for example, the A +2.2S value of the tablet of preparation 1 is 4.83, and the A +2.2S value of the tablet of preparation 11 is 4.16.

5. Dissolution measurement of tablets

The second method was used in 0931 of the four general rules of the year 2015, the "Chinese pharmacopoeia".

(1) Chromatographic conditions of the assay: the chromatographic column is C18 column, 150mm × 4.6mm, 5 μm; acetonitrile-0.1% formic acid solution (40:60) is used as a mobile phase; the flow rate is 1 ml/min; the detection wavelength was 230nm and the column temperature was 40 ℃. The relative standard deviation of the reference solution should not be greater than 1.0%, and the theoretical plate number should not be less than 5000 calculated according to Apremilast peak.

(2) Preparation of a test solution: using 900ml of phosphate buffer solution (taking 250ml of 0.2mol/L sodium dihydrogen phosphate solution and 116ml of 0.2mol/L sodium hydroxide solution to mix, adding 2g of SDS, diluting to 1000ml with water) as a dissolution medium, rotating at 75 revolutions per minute, taking 6 test samples after the temperature of the dissolution medium is constant at 37 +/-0.5 ℃, respectively putting the test samples into 6 dissolution cups, and immediately timing from the time when the test samples contact the dissolution medium. Taking out a proper amount of the dissolution liquid after 30 minutes, filtering, and taking the subsequent filtrate as a test solution.

(3) Preparation of control solutions: 20mg of an apremilast reference substance is precisely weighed, placed in a 20ml measuring flask, dissolved and diluted to the scale by acetonitrile and shaken up. Then, 1ml of the sample was precisely transferred into a 100ml volumetric flask and diluted with a dissolution medium to a solution containing about 10. mu.g of Apremilast per 1ml, thereby obtaining a control solution.

(4) The determination method comprises the following steps: 10 mul of each of the control solution and the sample solution is respectively injected into a liquid chromatograph, and the spectrogram is recorded.

(5) Calculating formula:

in the formula: v_{To pair}-dilution volume of control, ml; v_{Sample (A)}-the dilution volume of the test article, ml; a. the_{To pair}-the main peak area of the control;

A_{sample (A)}-the main peak area of the test sample; w_{To pair}-weight of control, mg.

(6) And (5) judging a result: generally, it is required that the elution amount of each of 6 tablets to be tested is not less than 75% (Q) of the labeled content, as calculated from the labeled content, for each batch of tablets to be tested. If only 1-2 of the 6 tablets are below the specified limit but not below the limit Q-10%, and the average elution amount is not below Q, the tablets can still be judged to be in accordance with the specification. If 1-2 of the 6 tablets are lower than Q, only 1 tablet is lower than Q-10% but not lower than Q-20%, and the average dissolving-out amount is not lower than Q, another 6 tablets should be taken for retesting; only 1-3 of the 12 pieces in the initial and secondary tests are lower than Q, wherein only 1 piece is lower than Q-10% but not lower than Q-20%. And the average elution amount is not less than Q, it can be judged as being in accordance with the specification. 10% and 20% shown in the above results indicate the percentage (%) relative to the indicated amount.

(7) Solution stability: the control solution and the test solution were stable for 36 hours at room temperature.

(8) As a result: the dissolution amount of each of the 6 tablets of all the test batches was within a range of 84% to 91% of the indicated content, for example, the dissolution amount of each of the 6 tablets of preparation example 1 was within a range of 87.1% to 89.4% of the indicated content, and the dissolution amount of each of the 6 tablets of preparation example 11 was within a range of 86.7% to 88.3% of the indicated content.

6. Determination of related substances

(1) The determination method comprises the following steps: taking a proper amount of fine powder of a sample to be detected, precisely weighing, adding a diluent (0.02% phosphoric acid-acetonitrile 70:30 solution) for dissolving and diluting to prepare 1ml of solution containing 0.5mg as a test solution; an appropriate amount of the above solution was precisely measured, and diluted with a diluent to a solution containing about 5. mu.g per 1ml, as a control solution. Respectively taking appropriate amount of impurity A and apremilast reference substance, precisely weighing, adding diluent to dissolve and dilute into solution containing 0.75 μ g of impurity and 0.5mg of apremilast per 1ml, and using as system applicability solution. Measuring by high performance liquid chromatography (0512 of the four-part general regulation of the Chinese pharmacopoeia 2015 edition), using octadecylsilane chemically bonded silica as a filler, using a column with the specification of 250mm multiplied by 4.6mm and 5 mu m, using acetonitrile-0.1% formic acid solution (40:60) as a mobile phase, measuring 10 mu l of system applicability solution precisely at the flow rate of 1ml/min and the detection wavelength of 240nm and the column temperature of 40 ℃, injecting the solution into a liquid chromatograph, recording a chromatogram, and ensuring that the separation degree of an Apremilast peak and an impurity A peak is not less than 1.5. Precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 3 times. Generally, it is required that the impurity A should not be larger than 3/20 (0.15%) in the main peak area of the control solution as calculated by the corrected peak area (multiplied by a correction factor of 1.36), the other individual impurity peak areas should not be larger than 1/10 (0.1%) in the main peak area of the control solution, and the sum of the impurity peak areas should not be larger than 3/5 (0.6%) in the main peak area of the control solution.

(2) And (3) measuring results: all the tablets of the detection batches have the impurity A less than 0.08 percent, other single impurities less than 0.04 percent, and the sum of the peak areas of all the impurities is within the range of 0.19-0.26 percent. For example, the impurity A of the tablet of preparation example 1 is 0.062%, the other single impurities are all less than 0.04%, and the sum of the peak areas of the impurities is 0.203%; preparation example 11 tablets had 0.058% of impurity a, less than 0.04% of the other individual impurities, and the sum of the peak areas of the individual impurities was 0.196%.

Test example 3 stability of Apremilast tablet

In this test example 3, stability tests were conducted on all of the tablets of 10mg size of preparation examples 1 to 6 and the tablets of 10mg size of preparation examples 11 to 15.

Stability sample keeping method, each batch of tablets was hermetically packed with an aluminum-plastic composite film simulating a commercial package, left at a temperature of 40 ℃ for 6 months, and then each performance parameter at 0 month (measured in test example 2 above) and 6 months was measured and compared for each batch of samples with reference to the method of test example 2.

The results are as follows:

1. properties of the tablets: at 6 months, all the tablets of the test batches appeared white or off-white, for example the tablet of preparation 11 was a white tablet.

2. Ultraviolet identification of tablets: at 6 months, all test batches of tablets had absorption maxima at wavelengths of 230, 342nm, for example, the tablet of preparation 11 had absorption maxima at wavelengths of 230.4, 341.7 nm.

3. Content determination of active ingredients of the tablets: at 6 months, the apremilast content of all the tablets in the detection batch is within the range of 97.5-99.3% of the marked amount; for a certain batch of tablets, the residual content of the active ingredient after the high-temperature treatment for 6 months is determined as the percentage obtained by dividing the content of the tablet for 6 months by the content of the tablet for 0 month and multiplying the percentage by 100 percent, and the result shows that the residual content of the apremilast at 6 months of all the tested batches of tablets is within the range of 96-99 percent, for example, the residual content of the tablet in preparation example 1 is 97.31 percent and the residual content of the tablet in preparation example 11 is 98.48 percent.

4. Dissolution rate determination of tablets: the elution amount of each of the 6 tablets of all the tablets of the test batches was within the range of 81% to 90% of the indicated content, for example, the elution amount of each of the 6 tablets of preparation example 1 was within the range of 85.3% to 87.1% of the indicated content, and the elution amount of each of the 6 tablets of preparation example 11 was within the range of 84.8% to 88.6% of the indicated content.

5. Determination of related substances: the impurity A of all the tablets of the detection batches is less than 0.11%, the other single impurities are less than 0.07%, and the sum of the peak areas of all the impurities is within the range of 0.23-0.31%. For example, the impurity a of the tablet of preparation 1 is 0.092% (48.4% increase relative to 0 months), the other individual impurities are each less than 0.06%, and the sum of the peak areas of the individual impurities is 0.274% (i.e., total impurity, 35.0% increase relative to 0 months); preparation example 11 tablet impurity a was 0.064% (10.3% increase over 0 months), other individual impurities were all less than 0.06%, and the sum of the peak areas of the individual impurities was 0.218% (i.e. total impurities, 11.2% increase over 0 months). For each batch of tablets, the substance results of 6 months are compared with 0 month, the increase percentage of the impurity A or the total impurities of 6 months is in a range of 44-57% in all the tablets of preparation examples 1-6, the increase percentage of the total impurities of all the tablets of preparation examples 1-6 is in a range of 32-44%, the increase percentage of the impurity A of all the tablets of preparation examples 11-15 is in a range of 8.7-12.3%, and the increase percentage of the total impurities of all the tablets of preparation examples 11-15 is in a range of 9.8-12.4% compared with the increase percentage of 0 month in the tablets of the batch. The trend of the above impurity a and total impurities shows that the stability of the tablets with the addition of phospholipid/calcium hydrogen phosphate is better.

The above-described embodiments are merely preferred embodiments for fully illustrating the present application, and the scope of the present application is not limited thereto. The equivalent substitution or change made by the person skilled in the art on the basis of the present application is within the protection scope of the present application. The protection scope of this application is subject to the claims.

Claims

1. An apremilast tablet comprising the following components: 10 parts of apremilast, 45-65 parts of lactose, 15-30 parts of microcrystalline cellulose, 2-4 parts of croscarmellose sodium, 0.5-1 part of magnesium stearate, 1-2 parts of phospholipid and 6-8 parts of calcium hydrophosphate; the phospholipid and the calcium hydrogen phosphate are added by the method of the following step (ia): (ia) spraying the Apremilast fine powder in a fluidized state, adding a phospholipid ethanol solution, adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain pre-treated Apremilast particles; in the phospholipid ethanol solution, the concentration of phospholipid in ethanol is 15-20%.

2. An apremilast tablet according to claim 1, wherein the apremilast tablet comprises, based on 10 parts by weight of apremilast, 50 to 65 parts by weight of lactose, 20 to 30 parts by weight of microcrystalline cellulose, 2 to 4 parts by weight of croscarmellose sodium, and 0.5 to 1 part by weight of magnesium stearate.

3. An apremilast tablet according to claim 1, wherein the apremilast tablet comprises, based on 10 parts by weight of apremilast, 55 to 62 parts by weight of lactose, 22 to 28 parts by weight of microcrystalline cellulose, 2.5 to 3.5 parts by weight of croscarmellose sodium, and 0.6 to 0.9 part by weight of magnesium stearate.

4. The apremilast tablet of claim 1, wherein the lactose is an anhydrate or monohydrate thereof.

5. The apremilast tablet of claim 1, wherein:

the apremilast is apremilast form a, which comprises diffraction peaks at about the following 2 theta angles in an XRD spectrum, as analyzed by X-ray powder diffraction: 8.1 +/-0.1, 14.4 +/-0.1, 15.2 +/-0.1, 17.4 +/-0.1, 18.4 +/-0.1, 19.2 +/-0.1, 20.5 +/-0.1, 22.8 +/-0.1, 23.2 +/-0.1, 23.6 +/-0.1, 24.5 +/-0.1 and 25.1 +/-0.1; or

The apremilast is apremilast form B, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 10.1 +/-0.1, 12.4 +/-0.1, 13.5 +/-0.1, 15.7 +/-0.1, 16.3 +/-0.1, 18.1 +/-0.1, 20.7 +/-0.1, 22.5 +/-0.1, 24.7 +/-0.1, 26.2 +/-0.1, 26.9 +/-0.1 and 29.1 +/-0.1; or

The apremilast is apremilast form C, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.5 +/-0.1, 11.3 +/-0.1, 15.3 +/-0.1, 16.4 +/-0.1, 17.8 +/-0.1, 21.4 +/-0.1, 22.6 +/-0.1, 23.5 +/-0.1, 24.8 +/-0.1, 25.5 +/-0.1, 26.4 +/-0.1 and 27.6 +/-0.1; or

The apremilast is apremilast form D, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.5 +/-0.1, 9.6 +/-0.1, 11.3 +/-0.1, 13.9 +/-0.1, 16.3 +/-0.1, 17.7 +/-0.1, 20.5 +/-0.1, 23.2 +/-0.1, 24.6 +/-0.1, 25.2 +/-0.1, 26.0 +/-0.1 and 28.8 +/-0.1; or

The apremilast is apremilast form E, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.6 +/-0.1, 9.2 +/-0.1, 11.4 +/-0.1, 15.5 +/-0.1, 16.5 +/-0.1, 17.9 +/-0.1, 19.6 +/-0.1, 20.5 +/-0.1, 21.6 +/-0.1, 22.8 +/-0.1, 23.8 +/-0.1 and 26.6 +/-0.1; or

The apremilast is apremilast form F, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 8.1 +/-0.1, 8.6 +/-0.1, 15.6 +/-0.1, 17.3 +/-0.1, 19.3 +/-0.1, 21.4 +/-0.1, 22.8 +/-0.1, 24.6 +/-0.1, 25.4 +/-0.1, 25.9 +/-0.1, 26.6 +/-0.1 and 27.7 +/-0.1; or

The apremilast is apremilast form G, which, when analyzed by X-ray powder diffraction, comprises diffraction peaks at about the following 2 Θ angles in the XRD spectrum: 7.9 plus or minus 0.1, 9.5 plus or minus 0.1, 11.7 plus or minus 0.1, 15.7 plus or minus 0.1, 16.8 plus or minus 0.1, 18.1 plus or minus 0.1, 19.7 plus or minus 0.1, 21.8 plus or minus 0.1, 22.8 plus or minus 0.1, 25.1 plus or minus 0.1, 25.8 plus or minus 0.1 and 26.7 plus or minus 0.1.

6. An apremilast tablet according to claim 1, wherein the surface of the tablet is further coated with a coating agent.

7. An apremilast tablet according to claim 6, wherein the weight of the coating layer is 2-10% of the weight of the core tablet.

8. An apremilast tablet according to claim 6, wherein the weight of the coating layer is 3-6% of the weight of the core tablet.

9. The apremilast tablet of claim 6, wherein the coating is a film coating material.

10. The apremilast tablet of claim 9, wherein the film coating material is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl hydroxyethyl cellulose, methylcellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinyl alcohol, and combinations thereof.

11. The apremilast tablet of claim 10, further comprising one or more of the following in the film coating material: talcum powder, titanium dioxide and a coloring agent.

12. The apremilast tablet of claim 11, the colorant being one or more selected from the group consisting of: ferric oxide, yellow ferric oxide, carmine, caramel, beta-carotene, sodium riboflavin phosphate, and aluminum lake.

13. The apremilast tablet of claim 6, wherein the coating is Eupatorium.

14. An apremilast tablet according to claim 13, wherein the amount of apremilast in a tablet is 5-50 mg.

15. An apremilast tablet according to claim 13, wherein the amount of apremilast in a tablet is 10-30 mg.

16. An apremilast tablet according to claim 13, comprising the active ingredient apremilast in an amount of 10mg, 20mg, 30mg per tablet.

17. An apremilast tablet according to claim 1, prepared by a process comprising the steps of:

(ia) spraying the Apremilast fine powder in a fluidized state, adding a phospholipid ethanol solution, adding calcium hydrophosphate fine powder after spraying, fluidizing and mixing, and removing ethanol to obtain pre-treated Apremilast particles;

(i) uniformly mixing the pretreated apremilast granules, lactose, microcrystalline cellulose and the croscarmellose sodium with the formula amount of 1/3-2/3, and preparing the granules by a dry method by using a compression roller device;

18. An apremilast tablet according to claim 1, wherein the phospholipid is selected from soy phospholipid or egg yolk lecithin.

19. An apremilast tablet according to claim 1, wherein dibasic calcium phosphate is anhydrous dibasic calcium phosphate.

20. A process for preparing an apremilast tablet according to any one of claims 1 to 19, comprising the steps of:

(iv) The resulting tablet cores are coated with a coating solution.

21. Use of an apremilast tablet according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of adult patients with active psoriatic arthritis, intermediate to severe plaque psoriasis suitable for phototherapy or systemic therapy, adult patients with oral ulcers associated with behcet's disease.