A pharmaceutical composition for treating psoriasis topically and a method for preparing the same

Abstract

The present application provides a pharmaceutical composition for treating psoriasis, which contains a certain amount of apremilast and choline-based ionic liquid, so that the medicine prepared therefrom can directly act on the skin surface, provide an effective concentration of apremilast at the action site, and increase the amount of apremilast penetrating into the skin. The present application also provides a preparation method of the pharmaceutical composition, and a medicine comprising the pharmaceutical composition.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition for the topical treatment of psoriasis. Background Technology

[0002] Psoriasis is a chronic inflammatory systemic disease characterized by epidermal hyperplasia and dermal inflammatory cell infiltration. Its typical feature is erythematous papules with thick, white scales. In severe cases, it can cause disabling psoriatic arthritis, significantly impacting patients' lives and imposing a huge economic burden on patients and their families. The incidence rate of psoriasis in the United States is approximately 2.7%, while in my country it is approximately 0.46%. Due to its stubborn and difficult-to-treat nature, it is considered a major research topic in dermatology worldwide and is one of the key diseases targeted for prevention and treatment globally. Traditional medications for psoriasis include drugs that regulate skin keratinization, such as acitretin, and immunosuppressants such as methotrexate and cyclosporine. However, some patients do not respond well to these medications or cannot tolerate their adverse reactions.

[0003] Apremilast (N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methanesulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}acetamide, chemical formula as follows:

[0004] It is an oral targeted therapy for psoriasis and is currently the only phosphodiesterase (PDE4) inhibitor used to treat plaque psoriasis. Clinically, it is mainly used to treat moderate to severe plaque psoriasis and psoriatic arthritis. Its main function is to block the degradation of AMP, leading to increased cAMP levels in PDE4-expressing cells, thereby interfering with the inflammatory response and immune system, and alleviating the inflammatory symptoms of psoriasis.

[0005] Psoriasis is a chronic inflammatory disease requiring long-term medication. However, oral apremilast tablets can cause gastrointestinal discomfort such as diarrhea, nausea, and vomiting. Furthermore, long-term oral apremilast may increase the risk of depression. A new topical administration method, acting directly on the skin surface, can reduce the dosage and systemic absorption of the drug, alleviating the gastrointestinal and systemic adverse reactions of apremilast. However, apremilast is insoluble in water and other polar solvents such as ethanol, has a large molecular weight, and poor transdermal penetration. Summary of the Invention

[0006] To overcome the problems of low solubility and poor transdermal penetration of apremilast, this invention provides a pharmaceutical composition for the topical treatment of psoriasis. The pharmaceutical composition contains a certain amount of apremilast and a choline-type ionic liquid, allowing the drug prepared from it to act directly on the skin surface, providing an effective concentration of apremilast at the site of action, and increasing the amount of apremilast penetrating into the skin. This invention also provides a method for preparing the pharmaceutical composition, and a drug comprising the pharmaceutical composition.

[0007] The present invention provides a pharmaceutical composition for the topical treatment of psoriasis, characterized in that the pharmaceutical composition comprises apremilast and a choline-type ionic liquid.

[0008] The inventors discovered that choline-type ionic liquids, prepared by reacting choline compounds with organic acids, can not only increase the solubility of apremilast but also act on the stratum corneum, increasing its permeability and thus enhancing the transdermal penetration of apremilast, achieving a localized and effective treatment for psoriasis. Here, both the choline compounds and organic acids are biodegradable and safe; the choline compounds, including choline hydroxide or choline bicarbonate, react with organic acids to produce water and / or carbon dioxide, which are easily removed, simplifying the process. In investigating the effect of choline-type ionic liquids on the solubility of apremilast, the inventors found that, due to the unique structure of the choline-organic acid reaction, choline-type ionic liquids with medium- to long-chain acid ligands exhibit significantly better solubility for apremilast than those with short-chain acid ligands. The cinnamic acid-choline ionic liquid formed by the reaction of cinnamic acid and choline hydroxide significantly improves the solubility of apremilast and also significantly increases its transdermal penetration. Furthermore, pharmacodynamic evaluation experiments show that the gel containing this composition exhibits significant therapeutic effects on psoriasis-like lesions and skin inflammation in mice, with minimal acute skin irritation. Therefore, the composition including apremilast and the cinnamic acid-choline ionic liquid can serve as an ideal topical treatment for psoriasis.

[0009] Preferably, the choline-type ionic liquid is prepared by reacting choline compounds with organic acids.

[0010] Preferably, the choline compound is selected from at least one of choline hydroxide and choline bicarbonate.

[0011] Preferably, the organic acid is selected from at least one of acetic acid, tartaric acid, geranilic acid, cinnamic acid, and oleic acid.

[0012] Preferably, the pharmaceutical composition includes apremilast and a choline-type ionic liquid prepared from choline hydroxide and cinnamic acid.

[0013] Preferably, in the choline-type ionic liquid, the molar ratio of choline compound to organic acid is 1:(1-2), for example, it can be 1:1, 1:1.5, 1:2, and more preferably 1:1.

[0014] Preferably, the mass fraction of apremilast in the pharmaceutical composition is 0.1% to 0.5%, for example, 0.1%, 0.2%, 0.3%, 0.4%, or 0.5%, more preferably 0.5%.

[0015] This invention also provides a method for preparing the above-mentioned pharmaceutical composition, the method comprising the following steps: mixing a choline compound with an organic acid and drying the mixture to obtain a choline-type ionic liquid; mixing apremilast with the choline-type ionic liquid to obtain the pharmaceutical composition. Here, after mixing the choline compound with the organic acid, the mixture is pre-frozen in a -80°C freezer for 10–24 hours and then dried in a vacuum freezing apparatus for 24–48 hours to obtain an anhydrous choline-type ionic liquid containing organic acid ligands.

[0016] The present invention also provides the use of the above-described pharmaceutical composition in the preparation of a topical treatment for psoriasis, wherein the drug may be administered transdermally in the form of a gel, patch, liquid, emulsion, or suspension for the treatment of skin diseases such as psoriatic arthritis, plaque psoriasis, atopic dermatitis, and inflammatory skin diseases.

[0017] The present invention also provides a medicament for the topical treatment of psoriasis, the medicament comprising the pharmaceutical composition described above. The medicament may further comprise pharmaceutically acceptable excipients. Here, pharmaceutically acceptable excipients are well known to those skilled in the pharmaceutical art and are determined based on the specific tissue to which the given pharmaceutical composition or dosage form will be applied; non-toxic and pharmaceutically acceptable excipients (e.g., water, acetone, ethanol, ethylene glycol, propylene glycol, 1,3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof) can be used to prepare gels, patches, liquids, emulsions, and suspensions. If desired, humectants or moisturizers may also be added to the pharmaceutical composition and dosage form. The medicament may be administered transdermally in the form of gels, patches, liquids, emulsions, or suspensions for the treatment of skin diseases including psoriatic arthritis, plaque psoriasis, atopic dermatitis, and inflammatory skin diseases.

[0018] Preferably, the drug comprises the pharmaceutical composition and hydroxypropyl methylcellulose (HPMC K4M), wherein the drug contains 0.04% to 0.1% apremilast, for example, 0.04%, 0.06%, 0.08%, or 0.1%. The drug can be prepared by heating a prescribed amount of water, adding HPMC K4M and stirring until dissolved, then adding a prescribed amount of the pharmaceutical composition to the solution and stirring until homogeneous to obtain the drug. The drug is applied directly to the skin surface in the form of a gel for topical treatment of psoriasis. For topical treatment of psoriasis, a daily dose of approximately 1–1000 mg is generally recommended, administered as a single dose once daily.

[0019] The beneficial effects of this invention are:

[0020] (1) The pharmaceutical composition provided by the present invention is simple to prepare, has controllable quality, and good reproducibility.

[0021] (2) In this pharmaceutical composition, the choline-type ionic liquid is biodegradable and has low toxicity, which can significantly increase the solubility of apremilast and the skin's permeability, so that the drug containing this pharmaceutical composition can act directly on the skin surface to achieve local treatment of psoriasis, avoiding the gastrointestinal or systemic toxic side effects of oral apremilast.

[0022] (3) When the drug composition is mixed with one or more pharmaceutical excipients, the resulting drug can achieve sustained-release and long-lasting treatment, and is convenient to administer, improving patient compliance and showing good application prospects. Attached Figure Description

[0023] Figure 1 The solubility of Apsera in choline-type ionic liquids of different concentrations is given.

[0024] Figure 2 The cumulative penetration-time curve of the gel of the drug composition over 24 hours.

[0025] Figure 3 For the pharmacodynamic evaluation of the drug composition in gel form.

[0026] Figure 4 H&E staining of rat skin 7 days after using a gel containing the drug composition. Detailed Implementation

[0027] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that, unless otherwise specified, the following embodiments and features can be combined with each other. Unless otherwise specified, the methods used in the embodiments of the present invention are conventional methods, and the reagents used are commercially available.

[0028] Example 1:

[0029] A pharmaceutical composition, the preparation method of which includes:

[0030] Acetic acid and choline hydroxide were mixed in a molar ratio of 1:1 and stirred at 50°C for 24 hours. After stirring, the mixture was pre-frozen at -80°C for 10 hours and dried using a vacuum freeze-drying apparatus for 48 hours to obtain an acetic acid-choline type ionic liquid. 50 mg of apremilast was added to 9.95 g of the above acetic acid-choline type ionic liquid, and the mixture was heated to 50°C and stirred until homogeneous to obtain composition 1.

[0031] Example 2:

[0032] Compared with Example 1, geraniol-choline type ionic liquid prepared by mixing tartaric acid and choline hydroxide in a molar ratio of 2:1 was used instead of acetic acid-choline type ionic liquid, and the rest was the same as in Example 1, to prepare composition 2.

[0033] Example 3:

[0034] Compared with Example 1, geraniol-choline type ionic liquid prepared by mixing geraniol and choline hydroxide in a molar ratio of 1:1 was used to replace acetic acid-choline type ionic liquid. The rest was the same as in Example 1, and composition 3 was prepared.

[0035] Example 4:

[0036] Compared with Example 1, a cinnamic acid-choline type ionic liquid prepared by mixing cinnamic acid and choline hydroxide in a molar ratio of 1:1 was used to replace the acetic acid-choline type ionic liquid. The rest was the same as in Example 1, and composition 4 was prepared.

[0037] Example 5:

[0038] Compared with Example 1, an oleic acid-choline type ionic liquid prepared by mixing oleic acid and choline hydroxide in a molar ratio of 1:1 was used instead of an acetic acid-choline type ionic liquid. The rest was the same as in Example 1, and composition 5 was prepared.

[0039] Example 6:

[0040] Composition 1 provided in Example 1 was used to prepare a gel for the topical treatment of psoriasis. The formula for preparing the gel is: 120g of composition 1, 4g of HPMC K4M, and 76g of purified water.

[0041] A gel for the topical treatment of psoriasis is prepared by the following method: purified water of the prescription amount is heated to 60°C, HPMC K4M is added and stirred until dissolved, and the prescription amount of composition 1 is added to the above solution and stirred evenly to obtain gel 1.

[0042] Example 7:

[0043] Compared with Example 6, Composition 2 was used to replace Composition 1 in the gel preparation formula and preparation method, while the rest was the same as in Example 6, and gel 2 was prepared.

[0044] Example 8:

[0045] Compared with Example 6, Composition 3 was used to replace Composition 1 in the gel preparation formula and preparation method, while the rest was the same as in Example 6, and gel 3 was prepared.

[0046] Example 9:

[0047] Compared with Example 6, Composition 4 was used to replace Composition 1 in the gel preparation formula and preparation method, while the rest was the same as in Example 6, and gel 4 was prepared.

[0048] Example 10:

[0049] Compared with Example 6, Composition 5 was used to replace Composition 1 in the gel preparation formula and preparation method, while the rest was the same as in Example 6, and gel 5 was prepared.

[0050] Comparative Example 1:

[0051] Aprepitant suspension gel preparation formula: Aprepitant 100mg, HPMC K4M 4g, purified water 96g.

[0052] An aprepitant suspension gel is prepared by the following method: the prescribed amount of purified water is heated to 60°C, HPMC K4M is added and stirred until dissolved, the prescribed amount of aprepitant is added to the above solution and stirred evenly to obtain the aprepitant suspension gel.

[0053] Comparative Example 2:

[0054] Blank gel preparation formula: HPMC K4M 4g, purified water 96g.

[0055] A blank gel is prepared by the following method: purified water of the prescribed amount is heated to 60°C, and HPMC K4M is added and stirred until dissolved to obtain a blank gel.

[0056]

Test Case 1 Structural Characteristic

[0057] Choline-type ionic liquids with different acid ligands were characterized using 1H NMR spectroscopy. A certain amount of each of the five choline-type ionic liquids with different acid ligands used in Examples 1-5 was weighed and placed in an NMR tube. Deuterated chloroform was added to dissolve and the mixture was shaken and mixed thoroughly. During the entire process, the NMR tubes must not come into contact with the bottom of the tube to avoid contamination. The NMR tubes were then sealed and sent to the NMR detector for 1H-NMR analysis of the five groups of ionic liquids. The results are shown in Table 1. The results indicate that the characteristic peaks are consistent with the hypothesized structure of choline-type ionic liquids, namely, the ratio of acid radicals to base ions in acetic acid-choline-type ionic liquids, geraniol-choline-type ionic liquids, cinnamic acid-choline-type ionic liquids, and oleic acid-choline-type ionic liquids is 1:1, while the ratio of acid radicals to base ions in tartaric acid-choline-type ionic liquids is 2:1.

[0058] Table 1. Characterization of cholinergic ionic liquids

[0059]

[0060]

[0061] [Test Example 2: Investigation of the solubility of Apster in choline-type ionic liquids]

[0062] The solubility of apremilast in water and choline-type ionic liquids with different concentrations of different acid ligands was determined using the shake-flask method. Excess apremilast was weighed into tubes, and a certain amount of the choline-type ionic liquid prepared in Examples 1-5 was added. The solutions were diluted with purified water to the desired concentration. Three replicates were prepared for each group. The tubes were shaken well, sealed, and placed in a constant-temperature shaking shaker at 32°C and 100 rpm for 72 h, ensuring the presence of solid drug throughout the equilibration process. After 72 h of equilibration, the tubes were removed, centrifuged at 9000 rpm for 10 min, and the supernatant was collected. The supernatant was filtered through a microporous membrane and diluted appropriately with the mobile phase acetonitrile-0.05% trifluoroacetic acid (52:48). The solubility of apremilast in different media was determined by high-performance liquid chromatography (HPLC). The results are shown in [Figure number missing]. Figure 1The results showed that apremilast has extremely low solubility in water, only 21.8 ± 3.8 μg / mL. Compared to water, the solubility of apremilast in 50% oleic acid-choline ionic liquid, cinnamic acid-choline ionic liquid, geraniol-choline ionic liquid, acetic acid-choline ionic liquid, and tartaric acid-choline ionic liquid increased by approximately 60.0, 240.3, 21.7, 1.21, and 0.9 times, respectively. These results indicate that choline ionic liquids significantly improve the solubility of apremilast. Ionic liquids with different acid ligands exhibit different solubility for different drugs, with cinnamic acid-choline ionic liquid showing the most significant effect. Furthermore, ionic liquids with medium- and long-chain acid ligands showed significantly better solubility than those with short-chain acid ligands.

[0063]

Test Example 3: Skin Penetration Test

[0064] Healthy female SD rats were euthanized by cervical dislocation. The skin on the rat's back was first roughly shaved with a razor, followed by a fine shave with a hand razor, taking care not to damage the stratum corneum during the shaving process. The back skin was then immediately peeled off. The skin was removed from the front of the rat's back, not extending beyond the forelimbs, and the dividing line between the front and back of the body was marked on both sides. The peeled skin was laid flat on a glass plate, and subcutaneous fat and connective tissue were removed with absorbent cotton. The skin was then repeatedly rinsed with physiological saline, and excess moisture was absorbed with filter paper. The skin was then laid flat on aluminum foil, cut into 1.5cm × 1.5cm squares, sealed in aluminum-plastic bags, and stored at -20℃ for later use.

[0065] Accurately take 4g of gels 1-5 prepared in Examples 6-10 or Aprestil suspension gel prepared in Comparative Example 1, and conduct an in vitro skin permeation experiment using a diffusion cell at 32°C. Before the experiment, check whether the mouse skin is intact. After confirming that it is intact, thaw the rat skin naturally in room temperature saline and clean it, then blot the surface moisture with filter paper. Fix the rat skin in the middle of the diffusion device, with the stratum corneum facing the supply cell. Use a certain amount of drug-ionic liquid solution as the supply solution and 20% PEG 400 as the receiving solution, and remove air bubbles to ensure sufficient contact between the receiving solution and the skin. At predetermined time intervals (0h, 4h, 6h, 8h, 10h, 24h), take 1mL of buffer sample from the receiving cell and immediately add an equal volume of buffer solution at the same temperature to the receiving cell to maintain the leakage conditions. The cumulative permeation-time curves of different gels over 24 hours are shown in the figure. Figure 2 .

[0066] Depend on Figure 2 It can be seen that the transdermal penetration of apremilast is relatively low; the cumulative penetration of the apremilast suspension gel provided in Comparative Example 1 was only 8.1 μg / cm³ over 24 hours. 2Among them, the gel agent 4 provided in Example 9 had the most significant permeation-enhancing effect, with its cumulative permeation amount in 24 hours being 10.6 times that of Example 1. Other examples did not have a significant permeation-enhancing effect, indicating that cinnamic acid-choline type ionic liquid has a significant effect on increasing the transdermal permeation of apremilast.

[0067] [Test Example 4: Pharmacodynamic Evaluation]

[0068] After shaving the back of rats, 5% imiquimod cream was applied to the back for 7 consecutive days to establish a psoriasis model. The psoriasis-infected rats were divided into three groups: a control group (using the blank gel prepared in Comparative Example 2), a drug group (using the apremilast suspension gel prepared in Comparative Example 1), and a combination group (using gel 4 prepared in Example 9). The rats were administered the drug for 7 consecutive days, and the PASI scores were assessed using the patient PASI standard, including lesion area and lesion severity scores. Psoriasis skin is characterized by three main features: erythema, infiltration, and scaling, evaluated using a 0-4 scale: 0 = none; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe. Erythema: Red or dark red inflammatory patches that blanch upon pressure. Infiltration: The lesions tend to spread outwards, with indistinct borders, and feel substantial upon pressure. Desquamation / scaling: The shedding of epidermal cells in sheets. PASI scoring results are shown below. Figure 3 The results showed that the gel 4 containing composition 4 prepared in Example 9 had a significant therapeutic effect on psoriatic lesions and skin inflammation in mice. The composition 4 was a cinnamic acid-choline type ionic liquid loaded with apremilast.

[0069] [Test Example 5: Tissue Toxicity]

[0070] Normal female rats were fasted for 12 hours, then their backs were shaved clean, and they were divided into three groups: a control group (using the blank gel prepared in Comparative Example 2), a drug group (using the apremilast suspension gel prepared in Comparative Example 1), and a composition group (using gel 4 prepared in Example 9). The sample gel was applied to the skin daily for 7 consecutive days, after which skin samples were harvested. The tissues were paraffin-embedded, sectioned, and observed under a microscope. The potential skin irritation of the transdermal formulation was evaluated by histopathological examination; the results are shown below. Figure 4 No inflammatory cell infiltration was observed in the epidermis and dermis of rats in the control group, drug group, and composition group. This suggests that the gel 4 containing apremilast and cinnamic acid-choline type ionic liquid composition 4 prepared in Example 9 has minimal acute skin irritation.

[0071] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for the topical treatment of psoriasis, characterized in that, The composition includes apremilast and a choline-type ionic liquid; the choline-type ionic liquid is prepared by reacting choline hydroxide and cinnamic acid in a molar ratio of 1:1; the mass fraction of apremilast is 0.1% to 0.5%.

2. A method for preparing the pharmaceutical composition as described in claim 1, characterized in that, The method includes the following steps: mixing choline hydroxide with cinnamic acid and drying to obtain a choline-type ionic liquid; mixing apremilast with the choline-type ionic liquid to obtain the pharmaceutical composition.

3. The use of the pharmaceutical composition according to claim 1 in the preparation of a topical treatment for psoriasis.

4. A topical treatment for psoriasis, characterized in that, The drug comprises the pharmaceutical composition as described in claim 1.

Images