Intestinal targeted drug delivery composition and preparation method thereof

Abstract

The invention discloses an intestinal targeted drug delivery composition which sequentially comprises (1) a pellet core and a non-pH dependent sustained-release layer containing an active ingredient, or a pellet containing an active ingredient and a non-pH dependent sustained-release layer, or a pellet containing an active ingredient and a non-pH dependent sustained-release material, (2) a pH dependent coating layer and (3) a time dependent pulse controlled-release layer from inside to outside. The intestinal targeted drug delivery composition delivers the active ingredients to intestinal tissues (especially colon tissues) for release, reduces the whole body blood concentration, and improves the pharmacokinetic characteristics of the active ingredients and the concentration of the active ingredients in the intestinal tissues. The composition is suitable for treating intestinal diseases, such as Crohn's disease, ulcerative colitis and other inflammatory bowel diseases.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and specifically relates to an intestinal targeted drug delivery composition and a preparation method thereof, and more specifically to an intestinal targeted drug delivery composition containing JAK inhibitors, hormones and / or other agents for treating intestinal diseases and a preparation method thereof. Background Art

[0002] Inflammatory bowel disease (IBD) is a special type of chronic inflammatory bowel disease, which mainly includes Crohn's disease (CD) and ulcerative colitis (UC).

[0003] JAK kinase belongs to the cytoplasmic tyrosine kinase family, which is considered to play an important role in inflammation. Inhibitors of the JAK kinase family have shown the efficacy of treating inflammatory diseases (e.g., inflammatory bowel diseases including ulcerative colitis and Crohn's disease) and autoimmune diseases. Upadacitinib is a highly efficient, selective and reversible JAK1 inhibitor, which is used to treat moderate to severe rheumatoid arthritis, psoriatic arthritis, moderate to severe ulcerative colitis, ankylosing spondylitis, Crohn's disease and other diseases. Tofacitinib is a JAK pathway inhibitor, which has been approved for the treatment of rheumatoid arthritis, and has good efficacy in the treatment of various autoimmune diseases such as ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, systemic lupus erythematosus and vitiligo.

[0004] However, studies have found that conventional formulations of JAK inhibitors for oral administration have the following limitations: the amount of the JAK inhibitors reaching the intestinal tract, such as the colon, is small, resulting in reduced efficacy; and due to the need for long-term medication and large adverse reactions, patient compliance is poor. Therefore, formulating JAK inhibitors into intestinal targeted delivery compositions has become the best choice.

[0005] Currently commonly used intestinal targeted drug delivery compositions mainly include pH-dependent intestinal targeted drug delivery compositions, time-delay-dependent intestinal targeted drug delivery compositions, and flora / enzyme-triggered intestinal targeted drug delivery compositions, etc. However, the digestive environment and mucosal transport mechanism of different parts of the gastrointestinal tract are quite different, and there are obvious differences between individuals. Gastric emptying is affected by food types and meal time. In particular, IBD patients have mucosal lesions and dietary changes, which change the factors that determine the pH value of the colon. The above-mentioned intestinal targeted oral preparations are difficult to truly achieve accurate colon-targeted release. Therefore, a new intestinal targeted drug delivery composition is needed to accurately deliver drugs to intestinal tissues, such as colon tissues, to achieve targeted release. SUMMARY OF THE INVENTION

[0007] On the one hand, the present application provides an intestinal targeted drug delivery composition, which comprises, from the inside to the outside, (1) a pellet core and a pH-independent sustained-release layer containing an active ingredient, or pellets containing an active ingredient and a pH-independent sustained-release layer, or pellets containing an active ingredient and a pH-independent sustained-release material, (2) a pH-dependent coating layer, and (3) a time-dependent pulse controlled-release layer.

[0008] On the other hand, the present application provides a method for preparing an intestinal targeted drug delivery composition, comprising the following steps:

[0009] (1) Preparation of pH-independent sustained-release layer

[0010] Adding active ingredients, sustained-release coating film-forming materials and one or more pharmaceutically acceptable excipients selected from plasticizers, pore-forming agents and anti-adhesive agents into an aqueous alcohol solution to form a sustained-release layer coating solution, and then coating blank pellet cores with the sustained-release layer coating solution to obtain sustained-release pellets;

[0011] or

[0012] The sustained-release coating film-forming material and one or more pharmaceutically acceptable excipients selected from plasticizers, pore-forming agents and anti-adhesive agents are added to an alcohol aqueous solution to form a sustained-release layer coating solution, and the active ingredients,

[0013] The binder and the filler are granulated to obtain drug-containing pellet cores, and then the drug-containing pellet cores are coated with the sustained-release layer coating solution to obtain sustained-release pellets;

[0014] or

[0015] Adding a sustained-release coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer, a pore-forming agent and an anti-adhesive agent into an aqueous solution of alcohol to form a sustained-release layer coating solution, coating a blank pill core with a solution containing an active ingredient and a binder to obtain a pill core containing a drug; and then coating the pill core containing a drug with the sustained-release layer coating solution to obtain sustained-release pellets;

[0016] or

[0017] Granulating the active ingredient, the binder, the filler, and the pH-independent sustained-release material to obtain sustained-release pellets containing the active ingredient and the pH-independent sustained-release material;

[0018] (2) Preparation of pH-dependent coating

[0019] The pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from plasticizers and anti-adhesive agents are added to an aqueous solution of alcohol to form a pH-dependent coating solution, and then the sustained-release pellets obtained in step (1) are coated with the pH-dependent coating solution to obtain

[0020] pH-dependent micropellets;

[0021] or

[0022] The pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from plasticizers and anti-adhesive agents are added to an aqueous solution of alcohol to form a pH-dependent coating solution, and then the sustained-release pellets obtained in step (1) are coated with the pH-dependent coating solution to obtain

[0023] pH-dependent micropellets;

[0024] The pH-dependent pellets are mixed with a filler, a disintegrant and / or a lubricant, and tabletted to obtain pH-dependent tablets;

[0025] or

[0026] The sustained-release pellets obtained in step (1) are mixed with a filler, a disintegrant and / or a lubricant, and compressed to obtain compressed tablets;

[0027] Adding a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent into an aqueous alcohol solution to form a pH-dependent coating solution, and coating the compressed tablet with the pH-dependent coating solution to obtain a pH-dependent tablet; and

[0028] (3) Preparation of time-dependent pulse controlled release layer

[0029] The osmotic control material and the osmotic regulation material are added to an aqueous solution of alcohol to form a time-dependent coating solution, and then the pH-dependent micropellets or the pH-dependent tablets are coated with the time-dependent coating solution to obtain the intestinal targeted drug delivery composition in the form of micropellets or tablets.

[0030] In another aspect, the present application provides use of the intestinal targeted drug delivery composition described above or the intestinal targeted drug delivery composition prepared by the method described above in the preparation of a drug for treating intestinal diseases, such as inflammatory bowel diseases including Crohn's disease and ulcerative colitis.

[0031] In another aspect, the present application provides a method for treating intestinal diseases, such as inflammatory bowel diseases including Crohn's disease and ulcerative colitis, comprising administering the intestinal targeted drug delivery composition described above or the intestinal targeted drug delivery composition prepared by the method described above to an individual in need thereof.

[0032] BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 A schematic structural diagram of the intestinal targeted drug delivery composition containing a drug of the present application in the form of a tablet is shown.

[0034] Figure 2 Another schematic structural diagram of the drug-containing intestinal targeted drug delivery composition of the present application in the form of a tablet is shown.

[0035] Figure 3 The dissolution curves of the intestinal targeted drug delivery compositions containing drugs prepared according to Comparative Examples 1 to 3 and Example 1 are shown.

[0036] Figure 4 The dissolution curves of the intestinal targeted drug delivery compositions containing drugs prepared according to Examples 1 to 4 are shown.

[0037] Figure 5 The drug plasma concentration-time curves of the intestinal targeted drug delivery compositions containing drugs prepared according to Comparative Example 1 and Comparative Example 2 in dogs are shown.

[0038] Figure 6 The drug plasma concentration-time curves of the intestinal targeted drug delivery compositions containing the drug prepared according to Comparative Example 3 and Example 1 in dogs are shown.

[0039] Figure 7 The drug concentration-time curves of the intestinal targeted drug delivery compositions containing drugs prepared according to Comparative Example 1 and Comparative Example 2 in the intestinal tissue of dogs are shown.

[0040] Figure 8 The drug concentration-time curves of the intestinal targeted drug delivery compositions containing drugs prepared according to Comparative Example 3 and Example 1 in the intestinal tissue of dogs are shown.

[0041] Fig. 9 The drug plasma concentration-time curves of the intestinal targeted drug delivery compositions prepared in Examples 1, 2 and 4 and conventional tablets of tofacitinib citrate in dogs after oral administration are shown.

[0042] Fig.10 The drug concentration-time curves of the intestinal targeted drug delivery composition prepared in Example 1 and conventional tablets of tofacitinib citrate in the intestinal tissue of dogs after oral administration are shown.

[0043] Detailed description

[0044] In one aspect, the present application provides an intestinal targeted drug delivery composition, which comprises, from the inside to the outside, a pH-independent sustained-release layer, a pH-dependent coating layer, and a time-dependent pulse controlled-release layer.

[0045] Specifically, the present application provides an intestinal targeted drug delivery composition, which comprises, from the inside to the outside, (1) a pellet core and a pH-independent sustained-release layer containing an active ingredient, or pellets containing an active ingredient and a pH-independent sustained-release layer, or pellets containing an active ingredient and a pH-independent sustained-release material, (2) a pH-dependent coating layer, and (3) a time-dependent pulse controlled-release layer.

[0046] Figure 1 and Figure 2 Two typical schematic diagrams of the intestinal targeted drug delivery composition containing a drug in the form of a tablet of the present application are shown respectively. Figure 1 In A, the drug-containing controlled-release pellets, which sequentially comprise a non-pH-dependent sustained-release layer and a pH-dependent coating layer from the inside to the outside, and the tablet coating formed by the core excipients have a time-dependent pulse controlled-release layer. Figure 2 In A, the tablets formed by the drug-containing sustained-release pellets comprising a non-pH-dependent sustained-release layer and the core excipients are sequentially coated with a pH-dependent coating layer and a time-dependent pulse controlled-release layer.

[0047] In some embodiments of the present application, the pH-independent sustained-release layer may be a sustained-release layer containing an active ingredient. Figure 1 B and Figure 2 As shown in B, the active ingredient is present in the pH-independent sustained-release layer. That is, the outer surface of the blank pellet core has a sustained-release layer containing the active ingredient. Alternatively, the active ingredient is mixed with the pH-independent sustained-release material and other suitable excipients, and granulated to form micropellets containing the active ingredient and the pH-independent sustained-release material.

[0048] In some embodiments of the present application, the non-pH-dependent sustained-release layer may be a sustained-release layer that does not contain an active ingredient. Figure 1 C and Figure 2 As shown in C, the active ingredient exists between the sustained-release layer and the blank pill core. That is, the outer surface of the blank pill core has an active ingredient layer and the sustained-release layer in sequence. Or, as Figure 1 D and Figure 2 As shown in D, the active ingredient is present in the pellet core to form a pellet core containing the drug, and the outer surface of the pellet core containing the drug has the sustained-release layer.

[0049] In addition, the drug-containing intestinal targeted drug delivery composition of the present application can be in the form of capsules or granules, which contain pellets that sequentially include a pH-independent sustained-release layer, a pH-dependent coating layer and a time-dependent pulse controlled-release layer from the inside to the outside, wherein the pH-independent sustained-release layer is a sustained-release layer containing or not containing an active ingredient as described above.

[0050] In some embodiments of the present application, the non-pH-dependent sustained-release layer comprises a sustained-release coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer, a pore-forming agent, and an anti-adhesive agent. In some embodiments of the present application, the non-pH-dependent sustained-release layer comprises a sustained-release coating film-forming material, a plasticizer, and one or more pharmaceutically acceptable excipients selected from a pore-forming agent and an anti-adhesive agent. In some embodiments of the present application, the non-pH-dependent sustained-release layer comprises a sustained-release coating film-forming material, a plasticizer, and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adhesive agent. In some embodiments of the present application, the non-pH-dependent sustained-release layer comprises a sustained-release coating film-forming material, a plasticizer, a pore-forming agent, and an optional anti-adhesive agent.

[0051] In some embodiments of the present application, the sustained-release coating film-forming material is selected from one or more of methacrylate copolymers, ethyl cellulose, hydroxypropyl methylcellulose and cellulose acetate; or, the sustained-release coating film-forming material is selected from one or more of ethyl cellulose, methacrylate copolymers and cellulose acetate; or, the sustained-release coating film-forming material is ethyl cellulose.

[0052] In some embodiments of the present application, the pH-independent sustained-release material is selected from one or more of methacrylate copolymers, ethyl cellulose, hydroxypropyl methylcellulose and cellulose acetate; or, the pH-independent sustained-release material is selected from one or both of ethyl cellulose and hydroxypropyl methylcellulose.

[0053] In some embodiments of the present application, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, diethyl or dibutyl phthalate, dibutyl sebacate, triethyl or tributyl citrate, acetyl tributyl citrate, castor oil, silicone oil and triethyl glycerol; or, the plasticizer is selected from triethyl citrate and triethyl glycerol; or, the plasticizer is triethyl citrate.

[0054] In some embodiments of the present application, the pore former is selected from one or more of polyethylene glycol, hypromellose, copovidone and povidone; or, the pore former is selected from polyethylene glycol and hypromellose; or, the pore former is hypromellose.

[0055] In some embodiments of the present application, the anti-adhesive agent is selected from one or more of talc, magnesium oxide, silicon dioxide and magnesium stearate; or the anti-adhesive agent is selected from talc and magnesium oxide.

[0056] In some embodiments of the present application, the pH-independent sustained-release layer comprises 50% to 80% of sustained-release coating film-forming material, 5% to 30% of plasticizer, 10% to 35% of pore-forming agent and 0% to 10% of anti-adhesive agent based on the total amount of sustained-release coating film-forming material, plasticizer, pore-forming agent and anti-adhesive agent by weight percentage. Those skilled in the art can easily determine the content of pH-independent sustained-release material in sustained-release micropellets according to the desired sustained-release effect.

[0057] In some embodiments of the present application, the pH-dependent coating layer may be a pH-dependent coating layer of about pH 5.5 to about pH 7.2. It will be appreciated by those skilled in the art that if a pH-dependent coating layer of about pH 5.5 is selected, the drug delivery composition may generally be targeted to the duodenum; if a pH-dependent coating layer of about pH 6.8 is selected, the drug delivery composition may generally be targeted to the small intestine; and if a pH-dependent coating layer of about pH 7.0 is selected, the drug delivery composition may generally be targeted to the colon. In some embodiments of the present application, the pH-dependent coating layer is a pH-dependent coating layer of about pH 7.0.

[0058] In some embodiments of the present application, the pH-dependent coating layer comprises a pH-dependent coating layer film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent.

[0059] In some embodiments of the present application, the pH-dependent coating film-forming material is selected from one or more of polymethacrylate, hydroxypropyl methylcellulose phthalate, polyacrylic acid resin and hydroxypropyl methylcellulose acetate succinate; or, the pH-dependent coating film-forming material is selected from one or more of hydroxypropyl methylcellulose phthalate and polyacrylic acid resin; or, the pH-dependent coating film-forming material is polyacrylic acid resin.

[0060] In some embodiments of the present application, the polyacrylic acid resin is EUDRAGIT, which is a general term for methacrylic acid copolymers and methacrylate copolymers, examples of which include EUDRAGIT RL-100, EUDRAGIT RS-100, EUDRAGIT E30D55, EUDRAGIT L30D-55, EUDRAGIT L-100, EUDRAGIT S-100, EUDRAGIT E 30D and EUDRAGIT E-100. EUDRAGIT L-100 dissolves in a solution with a pH value of >6, and EUDRAGIT S-100 dissolves in a solution with a pH value of >7.

[0061] In some embodiments of the present application, a layer of nonionic coating material can be coated as a barrier coating layer before coating the pH-dependent coating layer to prevent water penetration. If the pH-dependent coating layer is uniform and complete, it can prevent water penetration and the barrier coating layer is not required. The barrier coating layer comprises one or more of hydroxypropylmethylcellulose E5, hydroxypropylmethylcellulose E50, povidone K30, copovidone and Opadry.

[0062] In some embodiments of the present application, the plasticizer contained in the pH-dependent coating layer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, diethyl or dibutyl phthalate, dibutyl sebacate, triethyl or tributyl citrate, acetyl tributyl citrate, castor oil, silicone oil and triethyl glycerol; or, the plasticizer is selected from triethyl citrate and triethyl glycerol; or, the plasticizer is triethyl citrate.

[0063] In some embodiments of the present application, the pH-dependent coating comprises polymethacrylate (e.g., Eudragit L-100 and Eudragit S-100) as a pH-dependent coating film-forming material and one or more excipients selected from triethyl citrate, polyethylene glycol (e.g., PEG 6000) and diethyl or dibutyl phthalate as a plasticizer.

[0064] In some embodiments of the present application, the anti-adhesive agent contained in the pH-dependent coating layer is selected from one or more of talc, magnesium oxide, silicon dioxide and magnesium stearate.

[0065] In some embodiments of the present application, the pH-dependent coating layer comprises, by weight percentage, 50% to 90% of a pH-dependent coating layer film-forming material, 10% to 40% of a plasticizer, and 0-10% of an anti-adhesive agent.

[0066] In some embodiments of the present application, the pH-dependent coating layer can be coated on the outer surface of the pH-independent sustained-release layer, or the pH-dependent coating layer can be coated on the outer surface of a tablet containing a multi-particulate system containing the pH-independent sustained-release layer.

[0067] In some embodiments of the present application, the time-dependent pulse controlled-release layer can release the active ingredient after an appropriate time lag, for example, after 2-6 hours, 2-4 hours or 3-4 hours.

[0068] In some embodiments of the present application, the time-dependent pulse controlled-release layer comprises an osmotic control material and an osmotic regulating material.

[0069] In some embodiments of the present application, the permeation control material is selected from one or both of glyceryl behenate and ethyl cellulose. In some embodiments of the present application, the permeation control material is glyceryl behenate, or a mixture of glyceryl behenate and ethyl cellulose.

[0070] Glyceryl behenate may be present in the form of a monoester, a diester or a triester, or in the form of a mixture thereof. The HLB value of glyceryl behenate is preferably less than 5, more preferably about 2. In terms of weight percentage, the content of glyceryl behenate in the time-dependent pulse controlled release layer is about 5% to 85%, 10% to 70%, or 30% to 50%. Ethyl cellulose is a polymer material that is insoluble in water, acid or alkali and does not swell. In terms of weight percentage, the content of ethyl cellulose in the time-dependent pulse controlled release layer is 0.5% to 10% or 3% to 5%, provided that the total content of glyceryl behenate and ethyl cellulose in the time-dependent pulse controlled release layer is 10%-90%.

[0071] In some embodiments of the present application, the osmotic regulating material is selected from one or more of polyethylene glycol, hydroxypropyl methylcellulose, copolyvidone, povidone, polyoxyethylene ether-glyceryl butylene glycol ester, methyl silicone oil, zinc stearate, calcium stearate, aluminum stearate, sodium stearate, polysorbate, talc, and silicon dioxide. Polysorbate, such as polysorbate 80, can adjust the hydrophilicity of the controlled release layer. Talc is a hydrophilic excipient that has an anti-adhesive effect while adjusting the hydrophilicity.

[0072] In some embodiments of the present application, the time-dependent controlled-release layer comprises 10% to 90% of the osmotic control material and 10% to 90% of the osmotic adjustment material by weight percentage.

[0073] In some embodiments of the present application, the active ingredient contained in the intestinal targeted drug delivery composition of the present application can be a hydrophilic drug or a hydrophobic drug that needs to be administered to the intestine, for example, JAK inhibitors that need to be administered to the intestine, such as ruxolitinib, tofacitinib, baricitinib, upadacitinib, abrocitinib, filgotinib and their salts, and combinations thereof; and hormone drugs that need to be administered to the intestine, such as cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, triamcinolone acetonide and its salts, and combinations thereof.

[0074] On the other hand, the present application also provides a method for preparing the intestinal targeted drug delivery composition, which comprises the following steps:

[0075] (1) Preparation of pH-independent sustained-release layer

[0076] Adding active ingredients, sustained-release coating film-forming materials and one or more pharmaceutically acceptable excipients selected from plasticizers, pore-forming agents and anti-adhesive agents into an aqueous solution of alcohol to form a sustained-release layer coating solution, and then coating blank pellet cores with the sustained-release layer coating solution, for example, so that the coating weight increases by 20 wt% to 100 wt%, to obtain sustained-release pellets;

[0077] or

[0078] The sustained-release coating film-forming material and one or more pharmaceutically acceptable excipients selected from plasticizers, pore-forming agents and anti-adhesive agents are added to an alcohol aqueous solution to form a sustained-release layer coating solution, and the active ingredients,

[0079] The binder and filler are granulated to obtain a pill core containing medicine, for example, the particle size of the pill core containing medicine is 0.1-2 mm.

[0080] 0.2-1mm or 0.2-0.6mm; then coating the pill core containing the drug with the sustained-release layer coating solution, for example, so that the coating weight increases by 20wt% to 100wt%, to obtain sustained-release pellets;

[0081] or

[0082] Adding a sustained-release coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer, a pore-forming agent and an anti-adhesive agent into an aqueous solution of alcohol to form a sustained-release layer coating solution, coating a blank pill core with a solution containing an active ingredient and a binder to obtain a pill core containing a drug; then coating the pill core containing a drug with the sustained-release layer coating solution, for example, so that the coating weight increases by 20 wt% to 100 wt%, to obtain sustained-release pellets;

[0083] or

[0084] Granulating the active ingredient, the binder, the filler, and the pH-independent sustained-release material to obtain sustained-release pellets containing the active ingredient and the pH-independent sustained-release material;

[0085] (2) Preparation of pH-dependent coating

[0086] Adding a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent into an aqueous solution of alcohol to form a pH-dependent coating solution, and then coating the sustained-release pellets obtained in step (1) with the pH-dependent coating solution, for example, so that the coating weight increases by 5 wt% to 50 wt%, to obtain pH-dependent pellets;

[0087] or

[0088] Adding a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent into an aqueous solution of alcohol to form a pH-dependent coating solution, and then coating the sustained-release pellets obtained in step (1) with the pH-dependent coating solution, for example, so that the coating weight increases by 5 wt% to 50 wt%, to obtain pH-dependent pellets;

[0089] The pH-dependent pellets are mixed with a filler, a disintegrant and / or a lubricant, and tabletted to obtain pH-dependent tablets, for example, to obtain pH-dependent tablets with a hardness of 30 to 100 N;

[0090] or

[0091] The sustained-release pellets obtained in step (1) are mixed with a filler, a disintegrant and / or a lubricant, and compressed to obtain compressed tablets, for example, compressed tablets with a hardness of 30 to 100 N;

[0092] Adding a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent into an aqueous alcohol solution to form a pH-dependent coating solution, coating the compressed tablet with the pH-dependent coating solution, for example, to increase the coating weight by 5 wt% to 50 wt%, to obtain a pH-dependent tablet; and

[0093] (3) Preparation of time-dependent pulse controlled release layer

[0094] The osmotic control material and the osmotic regulating material are added to an aqueous solution of alcohol to form a time-dependent coating solution, and then the pH-dependent micropellets or the pH-dependent tablets are coated with the time-dependent coating solution, for example, so that the coating weight increases by 50wt% to 400wt%, to obtain the intestinal targeted drug delivery composition in the form of micropellets or tablets.

[0095] In some embodiments of the present application, in step (1), the sustained-release coating film-forming material, the plasticizer and the pore-forming agent, and optionally the anti-adherent agent are added to an aqueous alcohol solution.

[0096] In some embodiments of the present application, in step (2), a pH-dependent coating film-forming material, a plasticizer, and an optional anti-adherent agent are added to an aqueous alcohol solution.

[0097] In some embodiments of the present application, the blank pellet core is a microcrystalline cellulose pellet core, a silicon dioxide pellet core or a sucrose pellet core, or the blank pellet core is a microcrystalline cellulose pellet core and a silicon dioxide pellet core.

[0098] In some embodiments of the present application, the particle size of the blank pellet core is 0.1-2 mm, 0.2-1 mm or 0.2-0.6 mm.

[0099] In some embodiments of the present application, the adhesive used in step (1) of the above-mentioned preparation method is a pharmaceutical adhesive commonly used in the art, examples of which include but are not limited to one or more of starch slurry, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose.

[0100] In some embodiments of the present application, the filler is a pharmaceutical filler commonly used in the art, examples of which include but are not limited to one or more of microcrystalline cellulose, mannitol, sucrose, maltose, xylitol, lactose, glucose, starch and sorbitol. In some embodiments of the present application, the filler is microcrystalline cellulose and / or lactose.

[0101] In some embodiments of the present application, the disintegrant is a pharmaceutical disintegrant commonly used in the art, examples of which include but are not limited to one or more of low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and dry starch. In some embodiments of the present application, the disintegrant is selected from low-substituted hydroxypropyl cellulose and / or cross-linked carboxymethyl cellulose sodium.

[0102] In some embodiments of the present application, the lubricant is a pharmaceutical lubricant commonly used in the art, examples of which include but are not limited to one or more of magnesium stearate, micronized silica gel, talc, and hydrogenated vegetable oil. Preferably, the lubricant is selected from magnesium stearate.

[0103] In some embodiments of the present application, the alcohol used in the preparation method is an alcohol solvent commonly used in the art, examples of which include but are not limited to ethanol and isopropanol. In some embodiments of the present application, the aqueous solution of the alcohol is generally an aqueous solution of 95% ethanol, an aqueous solution of 90% ethanol, an aqueous solution of 95% isopropanol, an aqueous solution of 90% isopropanol, an aqueous solution of 5% ethanol, or an aqueous solution of 5% isopropanol.

[0104] In another aspect, the present application provides use of the intestinal targeted drug delivery composition in the preparation of a drug for treating intestinal diseases, such as inflammatory bowel diseases including Crohn's disease and ulcerative colitis.

[0105] In yet another aspect, the present application provides a method for treating intestinal diseases, such as inflammatory bowel diseases including Crohn's disease and ulcerative colitis, comprising administering the intestinal targeted drug delivery composition to an individual in need thereof.

[0106] The intestinal targeted drug delivery composition of the present application can absorb water and disintegrate after about 2-6 hours, 2-4 hours or 3-4 hours after oral administration, and can safely reach the small intestine through gastric juice, and release the active ingredient after entering the small intestine. Compared with existing oral preparations, the intestinal targeted drug delivery composition of the present application has one or more of the following advantages: it can accurately locate and release in intestinal tissue (such as colon tissue), reduce the systemic blood concentration of the active ingredient and reduce the blood exposure, improve the pharmacokinetics of the active ingredient and increase the concentration of the active ingredient in the intestinal tissue (such as colon tissue), enhance the therapeutic efficacy, improve safety, and reduce systemic toxicity, side effects and adverse reactions. Example

[0107] The present invention will be described in further detail below in conjunction with specific examples. These examples may be modified to obtain other embodiments without departing from the scope or spirit of the present invention. Therefore, the following examples are non-limiting.

[0108] Unless otherwise indicated, all numbers used in the specification and claims to represent feature sizes, quantities and physicochemical properties should be understood as being modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters listed in the above specification and the attached claims are approximate values, and those skilled in the art can use the teachings disclosed herein to seek to obtain the desired properties and appropriately change these approximate values. The use of numerical ranges expressed as endpoints includes all numbers within the range and any range within the range, for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4 and 5, etc.

[0109] The drugs or reagents used in this application, unless otherwise specified, are conventional commercial products. For example, Hydroxypropyl methylcellulose E5 was purchased from Dow Chemical Company, USA; Microcrystalline cellulose PH-101, Microcrystalline cellulose PH-102, low-substituted hydroxypropyl cellulose SH-LH21, Microcrystalline cellulose SH-101, Microcrystalline cellulose SH-102 and low-substituted hydroxypropyl cellulose SH-LH31 were purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; Eudragit L100, Eudragit S100 and Eudragit L30D-55 were purchased from Evonik Rohm Chemical (Shanghai) Co., Ltd.; Opadry film coating premix was purchased from Shanghai Colorcon Coating Technology Co., Ltd.

[0110] Comparative Example 1 (tablet containing only pH-independent sustained-release layer)

[0111] At room temperature, 5 g of tofacitinib citrate, 8 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of hydroxypropyl methylcellulose E5 were weighed and added to 150 g of 90% ethanol, stirred and dispersed evenly to prepare a sustained-release layer coating solution. 34 g of blank microcrystalline cellulose pellets were poured into a fluidized bed and coated with the sustained-release layer coating solution to prepare drug-containing sustained-release pellets.

[0112] The drug-containing sustained-release pellets, 38 g of microcrystalline cellulose PH-101, 38 g of microcrystalline cellulose PH-102, 14 g of low-substituted hydroxypropyl cellulose SH-LH21 and 1 g of magnesium stearate were mixed evenly. The tablets were pressed with a round deep concave punch to obtain tablets with a hardness of 40±10N.

[0113] Comparative Example 2 (tablet containing only pH-dependent coating layer)

[0114] At room temperature, 5 g of tofacitinib citrate and an appropriate amount of hypromellose E5 were weighed and added to 150 g of 90% ethanol, and stirred and dispersed evenly to prepare a drug-containing solution. 34 g of blank microcrystalline cellulose pellets were poured into a fluidized bed and sprayed with the drug-containing solution to obtain drug-containing pellets.

[0115] Weigh 4g Eudragit L100, 4g Eudragit S100, and 3g triethyl citrate into 150g 95% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the pill core containing the drug into a fluidized bed and coat it with the pH-dependent coating solution to obtain pH-dependent micropellets.

[0116] The pH-dependent pellets, 38 g of microcrystalline cellulose PH-101, 38 g of microcrystalline cellulose PH-102, 14 g of low-substituted hydroxypropyl cellulose SH-LH21 and 1 g of magnesium stearate were mixed evenly. The tablets were pressed with a round deep concave punch to obtain tablets with a hardness of 40±10N.

[0117] Comparative Example 3 (tablet containing only a time-dependent pulse controlled-release layer)

[0118] At room temperature, 5 g of tofacitinib citrate and an appropriate amount of hypromellose E5 were weighed and added to 150 g of 90% ethanol, and stirred and dispersed evenly to prepare a drug-containing solution. 34 g of blank microcrystalline cellulose pellets were poured into a fluidized bed and sprayed with the drug-containing solution to obtain drug-containing pellets.

[0119] The pellet core, 38 g of microcrystalline cellulose PH-101, 38 g of microcrystalline cellulose PH-102, 14 g of low-substituted hydroxypropyl cellulose SH-LH21 and 1 g of magnesium stearate were mixed evenly. The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0120] Weigh 10g of ethyl cellulose, 18g of hydroxypropyl methylcellulose E5, 9g of polysorbate 80, 178g of glyceryl behenate and 129g of talc into 2kg of 90% isopropanol, stir and disperse evenly to prepare a coating solution. Pour the compressed tablets into a high-efficiency coating pan and coat them with the coating solution to prepare tablets containing a time-dependent pulse controlled release layer.

[0121] Example 1

[0122] At room temperature, 5 g of tofacitinib citrate, 8 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of hydroxypropyl methylcellulose E5 were weighed and added to 150 g of 90% ethanol, stirred and dispersed evenly to prepare a sustained-release layer coating solution. 34 g of blank microcrystalline cellulose pellets were poured into a fluidized bed and coated with the sustained-release layer coating solution to prepare drug-containing sustained-release pellets.

[0123] Weigh 4g Eudragit L100, 4g Eudragit S100, and 3g triethyl citrate into 150g 95% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the drug-containing sustained-release pellets into a fluidized bed and coat them with the pH-dependent coating solution to prepare pH-dependent pellets.

[0124] Mix pH-dependent pellets, 38 g microcrystalline cellulose PH-101, 38 g microcrystalline cellulose PH-102, 14 g low-substituted hydroxypropyl cellulose SH-LH21, and 1 g magnesium stearate. Install the tablet press. The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0125] Weigh 10g of ethyl cellulose, 18g of hydroxypropyl methylcellulose E5, 9g of polysorbate 80, 178g of glyceryl behenate, and 129g of talc into 2kg of 90% isopropanol, stir and disperse evenly to prepare a coating solution. Pour the compressed tablets into a high-efficiency coating pan and coat them with the coating solution to prepare an intestinal targeted drug preparation.

[0126] Example 2

[0127] At room temperature, weigh 8g of cellulose acetate, 1.5g of triethyl citrate, and 3g of hydroxypropyl methylcellulose E5 and add them to 170g of 90% ethanol, stir and disperse them evenly to prepare a sustained-release layer coating solution. 5g of tofacitinib citrate, 4g of hydroxypropyl methylcellulose E5, and 30g of microcrystalline cellulose were wet granulated and extruded to obtain a drug-containing pellet core. The drug-containing pellet core was poured into a fluidized bed and coated with the sustained-release layer coating solution to obtain drug-containing sustained-release pellets.

[0128] Weigh 4g Eudragit L100, 4g Eudragit S100, and 3g triethyl citrate into 150g 95% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the drug-containing sustained-release pellets into a fluidized bed and coat them with the pH-dependent coating solution to prepare pH-dependent pellets.

[0129] Mix pH-dependent pellets, 30 g microcrystalline cellulose PH-101, 30 g microcrystalline cellulose PH-102, 10 g low-substituted hydroxypropyl cellulose SH-LH21, and 1 g magnesium stearate. Install the tablet press. The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0130] Weigh 12g ethylcellulose, 25g hydroxypropyl methylcellulose E15, 9g polysorbate 80, 150g behenic acid glyceryl, 100g talc and add to 2L 90% isopropanol, stir and disperse evenly to prepare coating solution. Pour the compressed tablets into a high-efficiency coating pan for coating to prepare a colon-targeted drug preparation.

[0131] Example 3

[0132] At room temperature, weigh 8g of cellulose acetate, 1.5g of triethyl citrate, and 3g of hydroxypropyl methylcellulose E5 and add them to 170g of 90% ethanol, stir and disperse them evenly, and prepare a sustained-release layer coating solution. Spray a suspended drug aqueous solution containing 5g of tofacitinib citrate and 4g of copovidone on the microcrystalline cellulose pellet core to prepare a drug-containing pellet core. Pour the drug-containing pellet core into a fluidized bed and coat it with the sustained-release layer coating solution to obtain drug-containing sustained-release micropellets.

[0133] Weigh 4g Eudragit L100, 4g Eudragit E100, and 3g triethyl citrate into 150g 95% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the drug-containing sustained-release micropellets into a fluidized bed and coat them with the pH-dependent coating solution to prepare pH-dependent micropellets.

[0134] Mix pH-dependent pellets, 35g microcrystalline cellulose SH-101, 35g microcrystalline cellulose SH-102, 15g low-substituted hydroxypropyl cellulose SH-LH31, and 1g magnesium stearate. Install the tablet press. The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0135] Weigh 10g ethyl cellulose, 18g hydroxypropyl methylcellulose E5, 9g polysorbate 80, 178g behenic acid glyceryl, 129g talc and add to 2kg 90% isopropanol, stir and disperse evenly to prepare coating solution. Pour the compressed tablets into a high-efficiency coating pan for coating to prepare a colon-targeted drug preparation.

[0136] Example 4

[0137] At room temperature, weigh 5g of tofacitinib citrate, 8g of ethyl cellulose, 2g of triethyl citrate, and 3g of hydroxypropyl methylcellulose E5 and add them to 150g of 90% ethanol, stir and disperse them evenly to prepare a sustained-release layer coating solution. Pour 34g of microcrystalline cellulose pellets into a fluidized bed and coat them with the sustained-release layer coating solution to prepare drug-containing sustained-release pellets.

[0138] Mix the drug-containing sustained-release pellets, 38g of microcrystalline cellulose PH-101, 38g of microcrystalline cellulose PH-102, 14g of low-substituted hydroxypropyl cellulose SH-LH31, and 1g of magnesium stearate. Install the tablet press The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0139] Weigh 4g Eudragit L100, 4g Eudragit S100, and 3g triethyl citrate into 150g 95% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the compressed tablets into a fluidized bed and coat them with the pH-dependent coating solution to prepare pH-dependent tablets.

[0140] Weigh 10g ethyl cellulose, 18g hydroxypropyl methylcellulose E5, 9g polysorbate 80, 178g behenic acid glyceryl, 129g talc and add to 2kg 90% isopropanol, stir and disperse evenly to prepare coating solution. Pour pH-dependent tablets into a high-efficiency coating pan for coating to prepare colon-targeted drug preparations.

[0141] Example 5

[0142] At room temperature, 5 g of tofacitinib citrate, 8 g of ethyl cellulose, 3 g of hypromellose E5, and 30 g of microcrystalline cellulose PH-101 were weighed and poured into a wet mixing granulator, and 20% ethanol was sprayed to prepare a wet soft material. The wet soft material was passed through an extrusion spheronizer to prepare drug-containing sustained-release pellets.

[0143] Weigh 4g Eudragit L100, 4g Eudragit S100, and 3g triethyl citrate into 150g 95% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the drug-containing sustained-release micropellets into a fluidized bed and coat them with the pH-dependent coating solution to prepare pH-dependent micropellets.

[0144] Mix pH-dependent pellets, 38 g microcrystalline cellulose PH-101, 38 g microcrystalline cellulose PH-102, 14 g low-substituted hydroxypropyl cellulose SH-LH21, and 1 g magnesium stearate. Install the tablet press. The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0145] Weigh 10g of ethyl cellulose, 18g of hydroxypropyl methylcellulose E5, 9g of polysorbate 80, 178g of glyceryl behenate, and 129g of talc into 2kg of 90% isopropanol, stir and disperse evenly to prepare a coating solution. Pour the compressed tablets into a high-efficiency coating pan and coat them with the coating solution to prepare an intestinal targeted drug preparation.

[0146] Example 6

[0147] The same operation as in Example 1 was performed to obtain compressed tablets.

[0148] Weigh 1g of allura red, 8g of ethyl cellulose, 18g of hydroxypropyl methylcellulose E5, 9g of polysorbate 80, 130g of glyceryl behenate, and 129g of talc into 2kg of 90% isopropanol, stir and disperse evenly to prepare a coating solution. Pour the compressed tablets into a high-efficiency coating pan for coating to prepare a colon-targeted drug preparation.

[0149] Example 7

[0150] The same operation as in Example 1 was performed to obtain compressed tablets.

[0151] Weigh 1g of allura red, 10g of ethyl cellulose, 18g of hydroxypropyl methylcellulose E5, 9g of polysorbate 80, 178g of glyceryl behenate, and 129g of talc into 2kg of 90% isopropanol, stir and disperse evenly to prepare a coating solution. Pour the compressed tablets into a high-efficiency coating pan for coating to prepare a colon-targeted drug preparation.

[0152] Example 8

[0153] The same operation as in Example 1 was performed to obtain compressed tablets.

[0154] Weigh 1g of allura red, 12g of ethyl cellulose, 18g of hydroxypropyl methylcellulose E5, 9g of polysorbate 80, 230g of glyceryl behenate, and 129g of talc into 2kg of 90% isopropanol, stir and disperse evenly to prepare a coating solution. Pour the compressed tablets into a high-efficiency coating pan for coating to prepare a colon-targeted drug preparation.

[0155] Example 9

[0156] At room temperature, 5 g of upadacitinib, 8 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of hydroxypropyl methylcellulose E5 were weighed and added to 150 g of 90% ethanol, and stirred and dispersed evenly to prepare a sustained-release layer coating solution. 34 g of blank microcrystalline cellulose pellets were poured into a fluidized bed and coated with the sustained-release layer coating solution to prepare drug-containing sustained-release pellets.

[0157] Weigh 4g Eudragit L100, 4g Eudragit S100, and 3g triethyl citrate into 150g 95% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the drug-containing sustained-release pellets into a fluidized bed and coat them with the pH-dependent coating solution to prepare pH-dependent pellets.

[0158] Mix pH-dependent pellets, 38 g microcrystalline cellulose PH-101, 38 g microcrystalline cellulose PH-102, 14 g low-substituted hydroxypropyl cellulose SH-LH21, and 1 g magnesium stearate. Install the tablet press. The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0159] Weigh 10g ethyl cellulose, 18g hydroxypropyl methylcellulose E5, 9g polysorbate 80, 178g behenic acid glyceryl, 129g talc and add to 2kg 90% isopropanol, stir and disperse evenly to prepare coating solution. Pour the compressed tablets into a high-efficiency coating pan for coating to prepare a colon-targeted drug preparation.

[0160] Example 10

[0161] At room temperature, 8g of prednisolone, 8g of ethyl cellulose, 2g of triethyl citrate, and 3g of hydroxypropyl methylcellulose E5 were weighed and added to 150g of 90% ethanol, and stirred and dispersed evenly to prepare a sustained-release layer coating solution. 34g of blank microcrystalline cellulose pellets were poured into a fluidized bed and coated with the sustained-release layer coating solution to prepare drug-containing sustained-release pellets.

[0162] Seal coating: Weigh Opadry film coating premix and purified water, add coating powder to purified water under stirring to prepare a coating solution with a concentration of 15% (W / W), and coat the sustained-release pellets to gain weight of about 3%. During the coating process, control the tablet bed temperature at 40±2℃. After the spraying is completed, set the air inlet temperature to 60±10℃ and the coating pan speed to 1-3rpm.

[0163] Weigh 30g Eudragit L30D-55, 5g triethyl citrate, and 15g talc into 150g 5% isopropanol, stir and disperse evenly to prepare a pH-dependent coating solution. Pour the drug-containing sustained-release micropellets coated with the isolation coat into the fluidized bed and coat them with the pH-dependent coating solution to prepare pH-dependent micropellets.

[0164] Mix pH-dependent pellets, 38 g microcrystalline cellulose PH-101, 38 g microcrystalline cellulose PH-102, 14 g low-substituted hydroxypropyl cellulose SH-LH21, and 1 g magnesium stearate. Install the tablet press. The tablets were compressed using a round deep concave punch to obtain a compressed tablet with a hardness of 40±10N.

[0165] Weigh 10g of ethyl cellulose, 18g of hydroxypropyl methylcellulose E5, 9g of polysorbate 80, 178g of glyceryl behenate, and 129g of talc into 2kg of 90% isopropanol, stir and disperse evenly to prepare a coating solution. Pour the compressed tablets into a high-efficiency coating pan and coat them with the coating solution to prepare an intestinal targeted drug preparation.

[0166] Performance Testing

[0167] The method used in this article to determine the in vitro dissolution and release rate is as follows: Take the product according to the dissolution and release test method (Appendix 0931 Method 1 of Part IV of the Chinese Pharmacopoeia 2020 Edition), use 900 ml of pH 5.5 phosphate buffer as the dissolution medium for the first 3 hours, and then use 900 ml of pH 7.2 phosphate buffer as the dissolution medium until all dissolved. The rotation speed is 100 revolutions per minute. The operation is carried out in accordance with the law. After 3 hours, 4 hours, 5 hours, 7 hours, 9 hours, 11 hours, 15 hours, and 19 hours, 5 ml of the solution is filtered and the filtrate is taken; according to the high performance liquid chromatography method (Appendix 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition), the release in different dissolution media is determined. The release amount in pH 5.5 phosphate buffer after 3 hours should not exceed 2%, the release amount in pH 7.2 phosphate buffer after 4 hours should be 15%-30%, the release amount in 7 hours should be 40%-60%, and the release amount in 19 hours should be more than 75%.

[0168] Unless otherwise specified, the amount of tofacitinib was determined using the following HPLC conditions:

[0169] Octadecylsilane bonded silica gel was used as filler; pH 6.8 phosphate buffer (about 1.3 g KH2PO4 and 5 ml triethylamine added to 1000 ml water, adjusted to pH 6.8 with H3PO4 when necessary) - acetonitrile (70:30) was used as mobile phase; the flow rate was 1.0 ml per minute; the detection wavelength was 289 nm; the column temperature was 35°C; the injection volume was 20 μl.

[0170] The methods described above and below were used to test the in vitro dissolution and in vivo pharmacokinetic properties of the pharmaceutical preparations prepared in the comparative examples and the examples, respectively. The experimental results are shown below.

[0171] Test Comparative Examples 1 to 3 and Example 1

[0172] (1) Dissolution curve measurement results

[0173] Table 1 Comparative results of in vitro dissolution tests of Examples 1 to 3 and Example 1

[0174] Serial number / time (h) 0 3 4 5 7 9 11 15 19 Comparative Example 1 0 35.25 44.53 52.36 66.55 75.98 81.34 86.35 88.56 Comparative Example 2 0 5.66 92.56 93.45 93.4 93.69 94.05 93.95 -- Comparative Example 3 0 0.11 90.21 91.56 92.51 92.15 93.05 93.46 -- Example 1 0 0.37 22.18 35.64 51.69 63.98 73.60 85.35 92.24

[0175] (2) Pharmacokinetics

[0176] This study adopted a single-dose single-dose regimen, selected 48 healthy Beagle dogs (24 males and 24 females, with a weight range of 12-16 kg at the time of administration), and randomly divided them into 4 groups. Each group was orally administered, and blood was collected and animals in each group were dissected at different time points after administration. The dosing regimen is shown in Table 2:

[0177] Table 2 Dosage regimen

[0178]

[0179] a Dosing concentrations were based on tofacitinib free base.

[0180] Intestinal tissue and content collection

[0181] Sampling frequency and time points: Blood was collected from the veins of the four limbs as shown in the time points in the table below. After blood collection, the animals were immediately anesthetized with Zotai 50 and xylazine hydrochloride, followed by femoral artery bleeding and sacrifice. Intestinal tissues and contents such as the duodenum, jejunum, ileum, cecum, and colorectum were collected.

[0182] Number of samples: All animals.

[0183]

[0184] Sample separation and storage

[0185] Blood sampling requirements and processing: Use EDTA-K2 anticoagulant tubes, and collect about 2 mL of blood from the limb veins each time. Centrifuge and separate plasma as soon as possible after blood collection. The plasma is first frozen and temporarily stored at about -20°C, and then transferred to the sample room refrigerator for further testing and analysis.

[0186] After tissue and contents were collected, the contents were washed with saline and then frozen at -20°C. Before analysis, tissue homogenate was prepared by homogenization method.

[0187] Biological sample analysis

[0188] After sampling, the drug concentration of tofacitinib in the samples was detected using the LC-MS / MS method.

[0189] Test conditions

[0190] Detection system: LC-MS / MS liquid phase tandem mass spectrometer (Thermo TSQ Quantem Discovery MAX)

[0191] HPLC column: Luna 3μm C18, S / N: H19-302624

[0192] Column temperature: 40°C

[0193] Autosampler temperature: room temperature

[0194] Mobile phase A: 0.1% formic acid in water (pH 6)

[0195] Mobile phase B: methanol

[0196] Needle washing solution: methanol: isopropanol: water (1:1:1)

[0197] Liquid phase ratio:

[0198]

[0199]

[0200] Ionization method: ESI+

[0201] Scan Mode: SRM

[0202] For quantitative analysis of precursor ions, fragment ions and collision energy (CE)

[0203]

[0204] Figure 5-Figure 8 The experimental results show that compared with the intestinal targeted drug preparations in Comparative Examples 1 to 3, the intestinal targeted drug preparation in Example 1 can be accurately delivered to the intestinal tissue, especially the colorectal tissue, to release the active ingredient.

[0205] Test Examples 1 to 4

[0206] (1) Dissolution curve measurement results

[0207] Table 3 Dissolution test results of Examples 1 to 4

[0208] Serial number / time (h) 0 3 4 5 7 9 11 15 19 Example 1 0 0.37 22.18 35.64 51.69 63.98 73.60 85.35 92.24 Example 2 0 0 22.85 34.25 47.99 58.59 67.00 78.52 85.46 Example 3 0 0 19.23 32.40 46.53 59.23 65.10 77.34 84.78 Example 4 0 0.22 15.96 30.41 50.15 63.85 73.78 84.65 90.42

[0209] (2) Pharmacokinetics

[0210] Experimental design

[0211] This study adopted a single-dose single-dose administration regimen, selected 30 healthy Beagle dogs (15 males and 15 females, weight range at the time of administration: 12-16 kg), and randomly divided them into 4 groups. Each group was orally administered with the intestinal targeted drug preparations in Examples 1, 2 and 4 and conventional tablets of tofacitinib citrate (control drug, tofacitinib citrate tablets, batch number: DE8535, specification: 5 mg, Pfizer), and blood was collected and animals in each group were dissected at different time points after oral administration. The administration regimen is shown in Table 4:

[0212] Table 4 Dosage regimen

[0213]

[0214]

[0215] a Dosing concentrations were based on tofacitinib free base.

[0216] Intestinal tissue and content collection

[0217] Sampling frequency and time points: Blood was collected from the veins of the four limbs as shown in the time points in the table below. After blood collection, the animals were immediately anesthetized with Zotai 50 and xylazine hydrochloride, followed by femoral artery bleeding and sacrifice. Intestinal tissues and contents such as the duodenum, jejunum, ileum, cecum, and colorectum were collected.

[0218] Number of samples: All animals.

[0219]

[0220] Sample separation and storage

[0221] Blood sampling requirements and processing: Use EDTA-K2 anticoagulant tubes, and collect about 2 mL of blood from the limb veins each time. Centrifuge and separate plasma as soon as possible after blood collection. The plasma is first frozen and temporarily stored at about -20°C, and then transferred to the sample room refrigerator for further testing and analysis.

[0222] After tissue and contents were collected, the contents were washed with saline and then frozen at -20°C. Before analysis, tissue homogenate was prepared by homogenization method.

[0223] Biological sample analysis

[0224] After sampling, the drug concentration of tofacitinib in the samples was detected using the LC-MS / MS method.

[0225] Test conditions

[0226] Detection system: LC-MS / MS liquid phase tandem mass spectrometer (Thermo TSQ Quantem Discovery MAX)

[0227] HPLC column: Luna 3μm C18, S / N: H19-302624

[0228] Column temperature: 40°C

[0229] Autosampler temperature: room temperature

[0230] Mobile phase A: 0.1% formic acid in water (pH 6)

[0231] Mobile phase B: methanol

[0232] Needle washing solution: methanol: isopropanol: water (1:1:1)

[0233] Liquid phase ratio:

[0234]

[0235] Ionization method: ESI+

[0236] Scan Mode: SRM

[0237] For quantitative analysis of precursor ions, fragment ions and collision energy (CE)

[0238]

[0239] Figure 9-10 The experimental results show that after oral administration, the local concentration of the intestinal targeted drug preparation in Example 1 in the intestinal tissue, especially the colorectal tissue, is higher than that of the conventional tablets of tofacitinib citrate; after oral administration, the exposure of the intestinal targeted drug preparations in Examples 1, 2 and 4 in plasma is lower than that of the conventional tablets of tofacitinib citrate.

[0240] Test Examples 6 to 8

[0241] (1) Observation of dissolution phenomenon

[0242] Use 900ml of pH 7.2 phosphate buffer as the medium, rotate the basket method at 100 revolutions, and observe the time it takes for the time-delay coat to disintegrate. (The time-delay coat contains allura red)

[0243] Serial number Time (h) Example 6 1.75h Example 7 3.17h Example 8 4.5h

Claims

1. An intestinal targeted drug delivery composition, which comprises, from the inside to the outside, (1) a pellet core and a pH-independent sustained-release layer containing an active ingredient, or pellets containing an active ingredient and a pH-independent sustained-release layer, or pellets containing an active ingredient and a pH-independent sustained-release material, (2) a pH-dependent coating layer, and (3) a time-dependent pulse controlled-release layer.

2. The composition according to claim 1, wherein the pH-independent sustained-release layer comprises a sustained-release coating film-forming material and one or more pharmaceutically acceptable excipients selected from plasticizers, pore-forming agents and anti-adhesive agents; or, the pH-independent sustained-release layer comprises a sustained-release coating film-forming material, a plasticizer and one or more pharmaceutically acceptable excipients selected from pore-forming agents and anti-adhesive agents; or, the pH-independent sustained-release layer comprises a sustained-release coating film-forming material, a pore-forming agent and one or more pharmaceutically acceptable excipients selected from plasticizers and anti-adhesive agents; or, the pH-independent sustained-release layer comprises a sustained-release coating film-forming material, a plasticizer and a pore-forming agent and optionally an anti-adhesive agent.

3. The composition according to claim 1 or 2, wherein the pH-dependent coating is a pH-dependent coating of pH 5.5 to pH 7.2, which comprises a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adhesive agent; or, the pH-dependent coating comprises a pH-dependent coating film-forming material and a plasticizer and optionally an anti-adhesive agent.

4. The composition according to any one of claims 1 to 3, wherein the time-dependent pulse controlled-release layer can release the active ingredient after a time lag of 2-6 hours, 2-4 hours or 3-4 hours, and comprises an osmotic control material and an osmotic regulating material.

5. The composition according to claim 2, wherein the sustained-release coating film-forming material is selected from one or more of methacrylate copolymers, ethyl cellulose, hydroxypropyl methylcellulose and cellulose acetate; or, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, diethyl or dibutyl phthalate, dibutyl sebacate, triethyl or tributyl citrate, acetyl tributyl citrate, castor oil, silicone oil and triethyl glycerol; or, the pore-forming agent is selected from one or more of polyethylene glycol, hydroxypropyl methylcellulose, copovidone and povidone; or, the anti-adhesive agent is selected from one or more of talc, magnesium oxide, silicon dioxide and magnesium stearate; or, the pH-independent sustained-release material is selected from one or more of methacrylate copolymers, ethyl cellulose, hydroxypropyl methylcellulose and cellulose acetate.

6. The composition according to claim 3, wherein the pH-dependent coating film-forming material is selected from one or more of polymethacrylate, hydroxypropyl methylcellulose phthalate, polyacrylic acid resin and hydroxypropyl methylcellulose acetate succinate; or, the plasticizer is selected from one or more of polyethylene glycol, glycerol, propylene glycol, diethyl or dibutyl phthalate, dibutyl sebacate, triethyl or tributyl citrate, acetyl tributyl citrate, castor oil, silicone oil and triethyl glycerol; or, the anti-adhesive is selected from one or more of talc, magnesium oxide, silicon dioxide and magnesium stearate.

7. The composition according to claim 4, wherein the penetration control material is selected from glyceryl behenate and / or ethyl cellulose; or, the penetration regulating material is selected from one or more of polyethylene glycol, hydroxypropyl methylcellulose, copovidone, povidone, polyoxyethylene ether-butylene glycol ester, methyl silicone oil, zinc stearate, calcium stearate, aluminum stearate, sodium stearate, polysorbate, talc, and silicon dioxide.

8. A composition according to any one of claims 2-7, wherein the pH-independent sustained-release layer comprises, by weight percentage, 50% to 80% of sustained-release coating film-forming material, 5% to 30% of plasticizer, 10% to 35% of pore-forming agent and 0% to 10% of anti-adhesive agent based on the total amount of sustained-release coating film-forming material, plasticizer, pore-forming agent and anti-adhesive agent; the pH-dependent coating comprises, by weight percentage, 50% to 90% of pH-dependent coating film-forming material, 10% to 40% of plasticizer and 0% to 10% of anti-adhesive agent; and the time-dependent controlled-release layer comprises, by weight percentage, 10% to 90% of permeation control material and 10% to 90% of permeation regulating material.

9. A method for preparing an intestinal targeted drug delivery composition, comprising the following steps: (1) Preparation of pH-independent sustained-release layer Adding active ingredients, sustained-release coating film-forming materials and one or more pharmaceutically acceptable excipients selected from plasticizers, pore-forming agents and anti-adhesive agents into an aqueous solution of alcohol to form a sustained-release layer coating solution, and then coating blank pellet cores with the sustained-release layer coating solution, for example, so that the coating weight increases by 20 wt% to 100 wt%, to obtain sustained-release pellets; or The sustained-release coating film-forming material and one or more drugs selected from plasticizers, pore-forming agents and anti-adhesive agents are mixed. The pharmaceutically acceptable excipients are added to the aqueous solution of alcohol to form a sustained-release coating solution, and the active ingredients, The binder and the filler are granulated to obtain a drug-containing pellet core, for example, the particle size of the drug-containing pellet core is 0.1-2 mm, 0.2-1 mm or 0.2-0.6 mm; then the drug-containing pellet core is coated with the sustained-release layer coating solution, for example, so that the coating weight increases by 20 wt% to 100 wt%, to obtain sustained-release pellets; or Adding a sustained-release coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer, a pore-forming agent and an anti-adhesive agent into an aqueous solution of alcohol to form a sustained-release layer coating solution, coating a blank pill core with a solution containing an active ingredient and a binder to obtain a pill core containing a drug; then coating the pill core containing a drug with the sustained-release layer coating solution, for example, so that the coating weight increases by 20 wt% to 100 wt%, to obtain sustained-release pellets; or Granulating the active ingredient, the binder, the filler, and the pH-independent sustained-release material to obtain sustained-release pellets containing the active ingredient and the pH-independent sustained-release material; (2) Preparation of pH-dependent coating Adding a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent into an aqueous solution of alcohol to form a pH-dependent coating solution, and then coating the sustained-release pellets obtained in step (1) with the pH-dependent coating solution, for example, so that the coating weight increases by 5 wt% to 50 wt%, to obtain pH-dependent pellets; or Adding a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent into an aqueous solution of alcohol to form a pH-dependent coating solution, and then coating the sustained-release pellets obtained in step (1) with the pH-dependent coating solution, for example, so that the coating weight increases by 5 wt% to 50 wt%, to obtain pH-dependent pellets; The pH-dependent pellets are mixed with a filler, a disintegrant and / or a lubricant, and tabletted to obtain pH-dependent tablets; or The sustained-release pellets obtained in step (1) are mixed with a filler, a disintegrant and / or a lubricant, and compressed to obtain compressed tablets; Adding a pH-dependent coating film-forming material and one or more pharmaceutically acceptable excipients selected from a plasticizer and an anti-adherent agent into an aqueous alcohol solution to form a pH-dependent coating solution, coating the compressed tablet with the pH-dependent coating solution, for example, so that the coating weight increases by 5 wt% to 50 wt%, to obtain a pH-dependent tablet; as well as (3) Preparation of time-dependent pulse controlled release layer The osmotic control material and the osmotic regulating material are added to an aqueous solution of alcohol to form a time-dependent coating solution, and then the pH-dependent micropellets or the pH-dependent tablets are coated with the time-dependent coating solution, for example, so that the coating weight increases by 50wt% to 400wt%, to obtain the intestinal targeted drug delivery composition in the form of micropellets or tablets.

10. Use of the intestinal targeted drug delivery composition according to any one of claims 1 to 8 or the intestinal targeted drug delivery composition prepared by the method according to claim 9 in preparing a drug for treating intestinal diseases, such as inflammatory bowel diseases including Crohn's disease and ulcerative colitis.

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