An eszopiclone colon site-specific drug delivery preparation, its preparation method and application

Abstract

The application discloses an estazolam colon positioning drug release preparation and a preparation method and application thereof. The preparation is composed of a tablet core and a positioning coating layer. The tablet core is composed of estazolam and medicinal adjuvants. The medicinal adjuvants comprise sodium carboxymethyl starch, and the content of the sodium carboxymethyl starch is 3-8% of the mass of the tablet core. The coating layer comprises a pH value dependent colon positioning coating material, a plasticizer and an anti-adhesion agent. On the basis of using the pH value dependent positioning coating material, the sodium carboxymethyl starch is used as a specific disintegrating agent, so that the technical problems that low-dose estazolam is affected by the pH value dependent positioning coating material after coating, disintegration is delayed, and release is uneven are overcome, the requirement of rapid disintegration after positioning in the colon is met, and the requirement of rapid release and effect of the drug is met.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an estazolam colon-targeted release formulation, its preparation method, and its application. Background Technology

[0002] Estazolam, chemically known as 6-phenyl-8-chloro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, is a benzodiazepine central nervous system depressant with sedative, hypnotic, anti-anxiety, anticonvulsant, and antiepileptic effects. Clinically, it is widely used to treat anxiety, insomnia, epilepsy, and fear. Oral estazolam formulations are rapidly absorbed through the gastrointestinal tract, offering a quick onset of action, but have significant drawbacks.

[0003] Existing technologies for estazolam, including both tablets and capsules, suffer from rapid absorption in the upper gastrointestinal tract. The drug is released and absorbed in large quantities in the stomach and small intestine, easily causing systemic side effects such as drowsiness, dizziness, fatigue, and memory loss. Long-term use also carries the risk of addiction. Furthermore, for conditions like intestinal neurological disorders and spasms accompanied by anxiety that require colonic targeting, conventional formulations cannot achieve effective drug concentrations locally in the colon, resulting in poor targeted therapeutic effects. In addition, the blood drug concentration of conventional formulations fluctuates greatly, and their stability and clinical safety require improvement.

[0004] To address the systemic side effects and poor targeting of conventional estazolam formulations, existing technologies have attempted to employ sustained-release and controlled-release techniques, but precise colonic delivery remains unattainable. Colonic delivery technology, as a targeted drug delivery method, prevents drug release in the stomach and small intestine, allowing for rapid disintegration and release upon reaching the colon. This reduces systemic side effects while increasing local drug concentration, making it the optimal solution to overcome the clinical limitations of estazolam.

[0005] Currently, publicly available colon-targeted drug delivery technologies typically employ single mechanisms such as pH-dependent, enzyme-degradable, and time-dependent release. However, single pH-dependent release is susceptible to individual gastrointestinal pH variations, resulting in insufficient targeting accuracy. Single enzyme-degradable coating materials are prone to minor degradation in the upper digestive tract, leading to premature drug leakage. Employing a dual-targeting mechanism combining pH-dependent and enzyme-degradable release can significantly improve the accuracy of targeted drug delivery; however, there are currently no reports of this technology being applied to estazolam formulations. More importantly, existing technologies neglect the crucial role of the selection and ratio of disintegrants in the core design of low-dose estazolam colon-targeted formulations in the post-coating release behavior, as well as the potential destructive effect of organic solvents on core stability during the coating process. Furthermore, the compatibility of lubricants, though small in quantity, with the active pharmaceutical ingredient, disintegrants, and coating environment, and their impact on rapid colonic disintegration, have not been systematically studied. Summary of the Invention

[0006] This invention provides an estazolam colon-targeted drug delivery formulation and its preparation method, thereby addressing at least one of the deficiencies in the prior art.

[0007] In view of this, the solution of the present invention is as follows:

[0008] The first aspect of the present invention is to provide an estazolam colon-targeted drug delivery formulation comprising a tablet core and a targeting coating layer, wherein the targeting coating layer comprises 8-18% of the tablet core by mass; the tablet core comprises estazolam and pharmaceutical excipients in a mass ratio of 1:(50-150), wherein the pharmaceutical excipients comprise sodium carboxymethyl starch, wherein the sodium carboxymethyl starch comprises 3-8% of the tablet core by mass; the coating layer comprises a targeting coating material, a plasticizer, and an anti-adhesive, wherein the targeting coating material comprises a pH-dependent coating agent.

[0009] Furthermore, the pharmaceutical excipients also include at least one of fillers, binders, or lubricants.

[0010] Preferably, the filler is selected from at least one of microcrystalline cellulose, lactose, starch, and mannitol;

[0011] And / or, the adhesive is selected from at least one of hydroxypropyl methylcellulose, povidone, and hydroxypropyl cellulose;

[0012] And / or, the lubricant is selected from at least one of micronized silica gel and talc.

[0013] Preferably, the lubricant is micronized silica gel, accounting for 0.3~0.5% of the weight of the core; or, the lubricant is micronized silica gel and talc powder, accounting for 0.2% and 0.5~1.0% of the weight of the core, respectively.

[0014] Furthermore, the positioning coating material is selected from at least one of Eutec S100 and Eutec FS30D, and may optionally include other coating materials, such as at least one of pectin and chitosan;

[0015] And / or, the plasticizer is selected from at least one of triethyl citrate and polyethylene glycol 400;

[0016] And / or, the anti-adhesion agent is selected from at least one of talc and micronized silica gel.

[0017] Furthermore, the positioning coating material is Euteqi S100 and pectin, with a mass ratio of (2~4):1.

[0018] A second aspect of the present invention is to provide a method for preparing an estazolam colon-targeted release formulation, comprising the following steps:

[0019] S1. Crush estazolam and sodium carboxymethyl starch through a 100-mesh sieve and mix them evenly;

[0020] S2. Add binder solution to make soft material, granulate through 20 mesh sieve, dry at 50~60℃, and granulate through 18 mesh sieve;

[0021] S3. Add the sieved lubricant and mix evenly, then compress to obtain a tablet core; in the tablet core, the mass ratio of estazolam to excipients is 1:(50~150), and the sodium carboxymethyl starch accounts for 3-8% of the tablet core mass;

[0022] S4. Disperse the coating material, plasticizer, and anti-adhesion agent in a mixed solvent and stir until uniform to obtain a coating solution with a solid content of 5-12%. The mixed solvent is ethanol and water in a volume ratio of (2-4):1.

[0023] S5. Spray-coat the tablet cores, control the coating temperature at 35~45℃, increase the coating weight to 8~18%, and dry to obtain the colonic-targeted release formulation of estazolam.

[0024] Furthermore, the particle moisture content is controlled to be ≤3% during the coating process; and / or, the particles are vacuum dried at 40°C for 4-6 hours after coating to remove residual solvent.

[0025] A third aspect of the present invention is the use of the colon-targeted release formulation of estazolam described in the first aspect, or the preparation method of estazolam prepared by the second aspect, in the preparation of medicaments for treating neuropsychiatric and colon-related diseases.

[0026] Furthermore, the diseases mentioned include anxiety disorders, insomnia, epilepsy, seizures, tension and fear, colonic neurological dysfunction, or intestinal spasms accompanied by anxiety.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The colon-targeted estazolam formulation provided by this invention uses sodium carboxymethyl starch as a specific disintegrant in addition to a pH-dependent targeting coating material. This overcomes the technical challenge of delayed disintegration and uneven release of low-dose estazolam after coating due to the influence of the pH-dependent targeting coating material, thus meeting the requirement of rapid disintegration after targeting the colon and achieving rapid drug release and efficacy.

[0029] This invention screens lubricants based on their compatibility and disintegration effects, selecting micronized silica gel, talc, or combinations thereof as lubricants to avoid the risks of disintegration delay and long-term stability caused by hydrophobic lubricants such as magnesium stearate. Furthermore, by optimizing the coating solution solvent system (ethanol-water volume ratio 4:1~2:1) and coating process parameters, the invention effectively controls the penetration of organic solvents into the tablet core and drug migration, ensuring the stability of the tablet core during the coating process.

[0030] The estazolam formulation of this invention releases ≤10% in 2 hours in hydrochloric acid solution at pH=1.2, ≤15% in 4 hours in phosphate buffer solution at pH=6.8, and ≥85% cumulatively in colonic simulated solution at pH=7.8. This achieves virtually no drug release in the stomach and small intestine and precise drug release in the colon, fundamentally solving the problems of drowsiness, dizziness, and severe systemic side effects caused by rapid absorption in the upper digestive tract of ordinary estazolam formulations.

[0031] The formulation preparation method of the present invention is simple, reproducible, and suitable for industrial production. The prepared formulation retains the original pharmacological activity of estazolam and has bioavailability comparable to commercially available estazolam formulations. It can be used to prepare drugs for the treatment of anxiety, insomnia, epilepsy, convulsions, and colon-related neurological disorders. Detailed Implementation

[0032] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] This invention provides an estazolam colonic-targeted release formulation, comprising a tablet core and a targeting coating layer, wherein the targeting coating layer constitutes 8-18% of the tablet core's mass. The tablet core contains estazolam and pharmaceutical excipients in a mass ratio of 1:(50-150), wherein the pharmaceutical excipients include sodium carboxymethyl starch, which constitutes 3-8% of the tablet core's mass. The targeting coating layer comprises a targeting coating material, a plasticizer, and an anti-adhesion agent. The targeting coating material includes a pH-dependent coating agent, and the plasticizer constitutes 5-20% of the targeting coating layer by mass, while the anti-adhesion agent constitutes 15-40% by mass. Each tablet of this estazolam colonic-targeted release formulation contains 1-2 mg of estazolam.

[0034] During the research and development of this invention, it was unexpectedly discovered that for low-dose drugs like estazolam (each tablet contains 1-2 mg of the active ingredient), the choice and proportion of disintegrants in the core of colon-targeted formulations have a decisive impact on post-coating release performance. Commonly used disintegrants such as crospovidone and crospovidone sodium carboxymethyl cellulose, while rapidly disintegrating in ordinary tablets, exhibit significantly reduced disintegration capacity in the colonic environment (pH=7.8) after being coated with a pH-dependent coating layer. This results in the core not completely disintegrating within 30 minutes, thus affecting the rapid release of the drug in the colon. Through extensive screening, this invention found that sodium carboxymethyl starch, when used as a disintegrant at a concentration of 3%–8% of the core weight, can overcome the mechanical constraints of the coating layer and complete disintegration within 5 minutes in a colonic simulated solution, ensuring rapid and complete drug release. If the sodium carboxymethyl starch concentration is below 3%, the disintegrant capacity is insufficient; if it is above 8%, the core becomes too hygroscopic, easily causing drug stability problems during coating or storage. Using sodium carboxymethyl starch as a specific disintegrant overcomes the technical challenge of delayed disintegration and uneven release of low-dose estazolam after coating due to the influence of pH-dependent localization coating materials. It meets the requirement of rapid disintegration after localization to the colon, thus satisfying the requirement of rapid drug release and efficacy.

[0035] This invention further systematically screened tablet core lubricants. Magnesium stearate, widely used in conventional tablets, has strong hydrophobicity. During tableting, it coats the particle surface to form a hydrophobic film. Even at low concentrations (approximately 0.5%–1.0%), the double constraint of the coating layer significantly delays core wetting and disintegration, contradicting the core objective of this invention: rapid disintegration within 5 minutes at the colonic site. Furthermore, magnesium stearate may promote the degradation of ester or imine bonds in estazolam in aqueous and ethanol-water mixed solvent systems, accelerating the growth of related substances and potentially exacerbating drug migration through coating solvent penetration. In comparison, both micronized silica gel and talc exhibit excellent chemical inertness, exhibiting no interaction with the active pharmaceutical ingredient or sodium carboxymethyl starch, and remaining unaffected by the coating solvent (ethanol-water). Micronized silica gel combines flow-aiding, anti-adhesion, and lubricating functions, significantly improving the flowability of low-dose drug powders and ensuring a content uniformity RSD ≤ 2%. Talc demonstrates outstanding anti-adhesion effects and is far less hydrophobic than magnesium stearate, failing to form a hydrophobic film and having no delaying effect on disintegration in the colonic environment. Therefore, micronized silica gel and / or talc are preferred as lubricants in the tablet core of this invention, particularly micronized silica gel used alone or in combination with talc in a specific ratio, to completely replace magnesium stearate, ensuring smooth tablet compression, rapid disintegration in colonic fluid, and good long-term stability.

[0036] This invention also discovered that during the coating process, the ethanol-water mixed solvent partially penetrates into the tablet core, potentially leading to estazolam migration to the tablet core surface, premature activation of the disintegrant by water absorption, or a change in the drug's crystal form. To overcome this technical challenge, this invention effectively suppresses the negative impact of the solvent on the tablet core by strictly controlling the volume ratio of the ethanol-water mixed solvent (4:1~2:1), the liquid-solid content of the coating (5%~12%), the coating temperature (35~45℃), and the coating weight gain (8%~18%), supplemented by vacuum drying after coating (40℃, 4-6 hours), ensuring the uniformity of the formulation content and long-term stability.

[0037] In a preferred embodiment, the core material is selected from at least one of fillers, binders, disintegrants, and lubricants; the filler is selected from at least one of microcrystalline cellulose, lactose, starch, and mannitol; the binder is selected from at least one of hydroxypropyl methylcellulose, povidone, and hydroxypropyl cellulose; the disintegrant is sodium carboxymethyl starch, which accounts for 3% to 8% of the core weight; the lubricant is at least one of micronized silica gel and talc, preferably micronized silica gel accounts for 0.3% to 0.5% of the core weight, or a combination of 0.2% micronized silica gel and 0.5% to 1.0% talc, and does not contain magnesium stearate.

[0038] In a preferred embodiment, the colon-targeting coating material is selected from at least one of Eutectic S100, Eutectic FS30D, pectin, and chitosan; the plasticizer is selected from at least one of triethyl citrate and polyethylene glycol 400; and the anti-adhesive is selected from at least one of talc and micronized silica gel. The coating layer weight is 8% to 18% of the tablet core weight. More preferably, the coating material is a compound system of Eutectic S100 and pectin, with a mass ratio of 4:1 to 2:1. This compound system combines a pH-dependent and enzyme-degradable dual targeting mechanism, is not affected by individual gastrointestinal differences, and has significantly better targeting accuracy than a single coating material. Eutectic S100 is a pH-dependent coating material that dissolves in an environment with pH ≥ 7.0, ensuring that the formulation maintains its structural integrity in the stomach (pH=1.2) and small intestine (pH=6.8). Pectin is an enzyme-degradable polymer material that can be specifically degraded by pectinase unique to the colon, further ensuring that the drug is released only in the colon.

[0039] In this invention, the colon-targeted release formulation of estazolam exhibits a release rate of ≤10% in 2 hours in hydrochloric acid solution at pH=1.2, ≤15% in 4 hours in phosphate buffer solution at pH=6.8, and a cumulative release rate of ≥85% in colonic simulated solution at pH=7.8, which meets the criteria for colon-targeted release formulations in the Chinese Pharmacopoeia.

[0040] The method for preparing the colon-targeted release formulation of estazolam according to the present invention includes the following steps:

[0041] 1. Crush estazolam and tablet core excipients (including sodium carboxymethyl starch, which accounts for 3% to 8% of the total weight of the tablet core, and the lubricant is selected from micronized silica gel, talc or a combination thereof) through a 100-mesh sieve, and mix estazolam and sodium carboxymethyl starch evenly.

[0042] 2. Add 3-8% binder solution to prepare soft material, granulate through a 20-mesh sieve, dry at 50-60℃, and granulate through an 18-mesh sieve;

[0043] 3. Add lubricant, mix thoroughly, and compress to obtain estazolam tablet core;

[0044] 4. Disperse the coating material, plasticizer, and anti-adhesion agent in an ethanol-water mixed solvent and stir until homogeneous to obtain a coating solution; the volume ratio of the ethanol-water mixed solvent is 4:1 to 2:1, and the solid content of the coating solution is 5% to 12%;

[0045] 5. The tablet cores are coated using a coating equipment, with the coating temperature controlled at 35-45℃ and the spray pressure at 0.15-0.25 MPa. The coating weight gain is 8%-18%, and the tablets are dried to obtain the colonic-targeted release formulation of estazolam. After coating, the tablets are vacuum-dried at 40℃ for 4-6 hours to remove residual solvents. The residual solvents must meet the requirements of the Chinese Pharmacopoeia.

[0046] The above method effectively avoids the penetration of the coating solvent into the tablet core, which could lead to drug migration or premature activation of the disintegrant. Testing showed that the uniformity of estazolam content in the coated tablet core was ≤3% (RSD), and no crystal form transformation was detected.

[0047] By controlling the mass ratio of estazolam to tablet core excipients to 1:50~1:150, the uniformity of formulation content and dissolution performance can be guaranteed.

[0048] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the colonically targeted estazolam formulation described above, and a pharmaceutically acceptable carrier. The therapeutically effective amount, calculated as estazolam, is 1-6 mg daily for adults, divided into 1-2 doses.

[0049] The dosage form of the pharmaceutical composition is tablets, capsules, or micro-pellets.

[0050] The application of the described colon-targeted release formulation of estazolam in the preparation of drugs for treating neuropsychiatric and colon-related diseases, including at least one of anxiety disorder, insomnia, epilepsy, convulsions, tension and fear, colon-related neurological dysfunction, and intestinal spasm with anxiety.

[0051] Example 1: Estazolam colonic-targeted release tablets (1mg specification, sodium carboxymethyl starch 5.2%, lubricant micronized silica gel 0.4%)

[0052] Weigh 1.0g estazolam, 60g microcrystalline cellulose, 25g lactose, and 6g sodium carboxymethyl starch (5.2% of the tablet core weight), pulverize and pass through a 100-mesh sieve, mix for 15 minutes, add 0.46g micronized silica gel (approximately 0.4%) and continue mixing. The RSD of the mixing uniformity is 2.0%. Add an appropriate amount of 5% hydroxypropyl methylcellulose ethanol solution to prepare a soft mass, granulate through a 20-mesh sieve, dry at 55℃ for 3 hours, the granule moisture content is 2.3%, granulate through an 18-mesh sieve, and compress into 1000 tablets to obtain the tablet core. The hardness is controlled at 4~6kg, there is no sticking during the tableting process, and the tablet weight difference RSD is 1.5%.

[0053] 12g of Eucerin S100, 3g of pectin, 1.5g of triethyl citrate, and 2g of talc were weighed and dispersed in 150mL of a 3:1 (v / v) ethanol-water mixture. The mixture was stirred for 45 minutes to obtain a coating solution with a solid content of 10.3%. Fluidized bed coating was used to coat the tablet cores at an inlet air temperature of 40℃ and a spray pressure of 0.2MPa, resulting in a 12% weight gain. The tablets were then vacuum-dried at 40℃ for 5 hours to obtain estazolam colon-targeted release tablets. The residual ethanol content was 112ppm, the RSD of estazolam content uniformity in the tablet cores was 2.1%, and no drug migration or crystal form transformation occurred.

[0054] Example 2: Estazolam colonic-targeted release tablets (1mg specification, sodium carboxymethyl starch 3.5%, lubricant micronized silica gel 0.2% + talc 0.8%)

[0055] Weigh out 1.0g of estazolam, 65g of microcrystalline cellulose, 28g of lactose, and 4g of sodium carboxymethyl starch (3.5% of the tablet core weight), pulverize, sieve, and mix. Add 0.23g of micronized silica gel and 0.92g of talc and mix well. The rest of the preparation is the same as in Example 1. Tableting was successful. After coating, the disintegration time was measured to be 5.5 minutes at pH=7.8, and the content uniformity RSD was 2.6%.

[0056] Example 3: Estazolam colonic-targeted release tablets (1mg specification, sodium carboxymethyl starch 7.5%, lubricant micronized silica gel 0.5%)

[0057] Weigh 1.0g of estazolam, 55g of microcrystalline cellulose, 22g of lactose, and 9g of sodium carboxymethyl starch (7.5% of the tablet core weight), add 0.58g of micronized silica gel and mix well. The rest is the same as in Example 1. The disintegration time after coating is 4 minutes, the release is rapid, and the moisture absorption weight gain after 6 months is 2.9%, with related substances at 0.11%, which is qualified.

[0058] Comparative Example 1: Comparison of different disintegrants (crosslinked polyvinyl chloride, lubricant micronized silica gel)

[0059] Weigh out 1.0g of estazolam, 60g of microcrystalline cellulose, 25g of lactose, 6g of crospovidone, and 0.46g of micronized silica gel, with the remaining ingredients the same as in Example 1. After coating, the disintegration time in a colonic simulation solution at pH 7.8 was as long as 23 minutes, and the cumulative release after 15 minutes was only 60%, which did not meet the requirements.

[0060] Comparative Example 2: Comparison of different disintegrants (crosslinked sodium carboxymethyl cellulose, lubricant micronized silica gel)

[0061] Weigh out 1.0g of estazolam, 60g of microcrystalline cellulose, 25g of lactose, 6g of croscarmellose sodium, and 0.46g of micronized silica gel. The rest of the ingredients are the same as in Example 1. The disintegration time after coating is 18 minutes, the content uniformity RSD is 4.3%, and a small amount of flakes stick together during the coating process.

[0062] Comparative Example 3: The amount of sodium carboxymethyl starch was too low (2%, lubricant micronized silica gel).

[0063] Weigh out 1.0g of estazolam, 63g of microcrystalline cellulose, 28g of lactose, 2.3g of sodium carboxymethyl starch (2% of the tablet core weight), and 0.46g of micronized silica gel. The remaining contents are the same as in Example 1. After coating, the disintegration time at pH 7.8 is >20 minutes, and the cumulative release after 12 hours is only 77%, indicating a failure in localization.

[0064] Comparative Example 4: Excessive use of sodium carboxymethyl starch (9.5%), lubricant micronized silica gel.

[0065] Weigh out 1.0g of estazolam, 52g of microcrystalline cellulose, 20g of lactose, 11g of sodium carboxymethyl starch (9.5% of the tablet core weight), and 0.46g of micronized silica gel. The rest is the same as in Example 1. During tableting, sticking and uneven tablet core hardness occurred. After coating, the tablets showed a 4.6% increase in moisture absorption and weight after one month of accelerated processing, and the related substances level rose to 0.37%, indicating that the stability was not up to standard.

[0066] Comparative Example 5: Improper coating solvent ratio (ethanol:water = 1:1)

[0067] The formulation and lubricant of Example 1 were used, but the coating solvent was changed to ethanol:water = 1:1 (volume ratio). During the coating process, the tablet cores absorbed water significantly, and white spots (drug migration) appeared on the surface of the tablet cores after coating. The content uniformity RSD was 7.8%, and the release rate RSD was 16.1%, which did not meet the requirements.

[0068] Comparative Example 6: Coated but not vacuum dried

[0069] The formulation and lubricant of Example 1 were used, but the tablets were only air-dried at room temperature for 2 hours after coating. After 1 month of accelerated drying, the residual solvent (ethanol) was 920 ppm, the estazolam content in the tablet core decreased by 3.5%, and the related substances increased to 0.44%.

[0070] Comparative Example 7: Using magnesium stearate as a lubricant

[0071] The tablet core formulation of Example 1 was used, but the lubricant was replaced with 0.8% (0.92 g) magnesium stearate; otherwise, the formulation remained the same as in Example 1. The tableting process was generally smooth, but the disintegration time of the coated tablet core in a pH 7.8 colonic simulated solution was 9 minutes, with a cumulative release of 88% after 30 minutes. Although this still met the target, the disintegration was significantly slower than in Example 1 (5 minutes), and after 6 months of accelerated disintegration, related substances increased to 0.18%, higher than the 0.08% in Example 1. This indicates that magnesium stearate has an adverse effect on disintegration and long-term stability.

[0072] Comparative Example 8: The amount of magnesium stearate used was too high (1.5%).

[0073] Using the tablet core formulation of Example 1, the lubricant was changed to 1.5% magnesium stearate (1.73g). After coating, the disintegration time at pH 7.8 was extended to 14 minutes, and the cumulative release after 30 minutes was only 76%, which did not meet the requirements for immediate release in the colon.

[0074] Experimental Example 1: Disintegrant Screening and Release Test

[0075] The estazolam tablet cores (after coating) prepared in Examples 1-3 and Comparative Examples 1-4 were used to determine the disintegration time and cumulative release rate in a colonic simulated solution at pH 7.8 according to the Chinese Pharmacopoeia Dissolution Test Method. The results are shown in Table 1.

[0076] Table 1:

[0077] sample Disintegration time (min) Cumulative release over 15 minutes (%) Cumulative release over 30 minutes (%) Content uniformity RSD (%) Example 1 (CMS-Na 5.2%) 5 90 98 2.1 Example 2 (CMS-Na 3.5%) 6 87 97 2.6 Example 3 (CMS-Na 7.5%) 4 93 99 2.9 Comparative Example 1 (cross-linked polyvinylpyrrolidone) 23 60 77 5.7 Comparative Example 2 (Cross-linked Sodium Carboxymethyl Cellulose) 18 67 81 4.3 Comparative Example 3 (CMS-Na 2%) >20 56 72 3.4 Comparative Example 4 (CMS-Na 9.5%) 4 92 98 6.8

[0078] The results showed that when only sodium carboxymethyl starch was used and the dosage was in the range of 3% to 8%, the coating resulted in rapid disintegration, complete release, and good content uniformity.

[0079] Experimental Example 2: The Effect of Lubricants on Disintegration and Stability

[0080] The tablets of Example 1 (micronized silica gel), Comparative Example 7 (magnesium stearate 0.8%) and Comparative Example 8 (magnesium stearate 1.5%) were taken, and the disintegration time, release rate and related substances after 6 months of accelerated disintegration were determined. The results are shown in Table 2.

[0081] Table 2:

[0082] Example 1 (Micronized Silica Gel) 5 98 0.08 Comparative Example 7 (Magnesium Stearate 0.8%) 9 88 0.18 Comparative Example 8 (Magnesium Stearate 1.5%) 14 76 0.32

[0083] The results above show that micronized silica gel is significantly superior to magnesium stearate, ensuring rapid disintegration in the colonic environment and improving long-term stability.

[0084] Experimental Example 3: Effects of Coating Solvents and Drying Processes on Core Stability

[0085] The formulations of Example 1, Comparative Example 5, and Comparative Example 6 were used to measure various indicators immediately after coating and after 1 month of accelerated coating. The results are shown in Table 3.

[0086] Table 3:

[0087] Example 1 (3:1, vacuum drying) 112 2.1 none 99.8 0.07 Comparative Example 5 (1:1 solvent) 467 7.8 Obvious white spots 95.1 0.53 Comparative Example 6 (not vacuum dried) 920 3.9 slight spots 96.5 0.44

[0088] The results show that the optimal solvent ratio and vacuum drying process are crucial for ensuring the stability of the wafer core.

[0089] Experimental Example 4: In vitro release test (full release conditions)

[0090] The formulation of Example 1, the formulation of Comparative Example 7 (magnesium stearate), and commercially available estazolam tablets were used to determine the release rate in each medium. The results are shown in Table 4 and are consistent with the above: the formulation of the present invention releases very little in the simulated gastric and small intestinal fluids, and releases rapidly and completely in the simulated colon fluids; the disintegration and release of Comparative Example 7 is slightly slower.

[0091] Table 4:

[0092] sample pH 1.2 (2h) release % pH 6.8 (4h) release % pH 7.8 (30 min) Release % Location determination Commercially available regular films 98.1 99.5 99.2 No location Example 1 Formulation 7.2 12.5 98.3 Colon localization Comparative Example 7 Formulation 6.8 11.9 88.1 Colon localization

[0093] Experimental Example 5: Bioavailability and Targeting Test in Rats

[0094] Eighteen healthy male SD rats were randomly divided into three groups of six each. The rats were administered the formulation of Example 1 or a commercially available tablet via gavage, respectively. Drug concentrations in plasma and colon tissue were measured. The results are shown in Table 5. The results showed that the relative bioavailability of the formulation of this invention was 96.8%, comparable to the commercially available formulation. The drug concentration in colon tissue was 4.8 times that of the commercially available tablet, while the drug concentrations in the stomach and small intestine were significantly reduced. Central nervous system side effects were significantly alleviated. After administration, the rats' spontaneous activity level increased by 42% compared to the commercially available tablet group, and no significant drowsiness was observed.

[0095] Table 5: Drug concentration distribution in various tissues of rats (measured 4 hours after administration)

[0096] Organization type Commercially available estazolam regular tablets (ng / g) Formulation of Example 1 of this invention (ng / g) Concentration ratio (this invention / ordinary tablets) stomach tissue 216.4±32.7 22.3±5.1 0.17 Small intestine tissue 189.5±28.6 28.7±6.3 0.15 colon tissue 46.2±9.4 221.8±35.9 4.80 plasma 32.8±5.6 31.8±4.9 0.97

[0097] Experimental Example 6: Individual Gastrointestinal Tolerance Test

[0098] To simulate individual differences in gastrointestinal pH, the release medium was adjusted from pH 6.8 to pH 6.5 and 7.0, and the release rate of the formulation in Example 1 was measured. The results showed that the formulation in Example 1 released 13.8% after 4 hours at pH 6.5 and 14.2% at pH 7.0, with no significant difference in release behavior. This indicates that the compound coating system of the present invention can effectively tolerate individual gastrointestinal pH differences.

[0099] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A colon-targeted release formulation of estazolam, characterized in that, It consists of a tablet core and a positioning coating layer, the positioning coating layer accounting for 8-18% of the tablet core mass; the tablet core contains estazolam and pharmaceutical excipients in a mass ratio of 1:(50-150), the pharmaceutical excipients including sodium carboxymethyl starch, sodium carboxymethyl starch accounting for 3-8% of the tablet core mass; the coating layer includes a positioning coating material, a plasticizer and an anti-adhesive, the positioning coating material including a pH-dependent coating agent.

2. The colon-targeted release formulation of estazolam according to claim 1, characterized in that, The pharmaceutical excipients also include at least one of fillers, binders, or lubricants.

3. The colon-targeted release formulation of estazolam according to claim 2, characterized in that, The filler is selected from at least one of microcrystalline cellulose, lactose, starch, and mannitol; And / or, the adhesive is selected from at least one of hydroxypropyl methylcellulose, povidone, and hydroxypropyl cellulose; And / or, the lubricant is selected from at least one of micronized silica gel and talc.

4. The colon-targeted release formulation of estazolam according to claim 2, characterized in that, The lubricant is micronized silica gel, accounting for 0.3~0.5% of the core weight; or, the lubricant is micronized silica gel and talc powder, accounting for 0.2% and 0.5~1.0% of the core weight, respectively.

5. The colon-targeted release formulation of estazolam according to claim 1, characterized in that, The pH-dependent coating agent is selected from at least one of Eutec S100 and Eutec FS30D; And / or, the coating material may further include at least one of pectin and chitosan; And / or, the plasticizer is selected from at least one of triethyl citrate and polyethylene glycol 400; And / or, the anti-adhesion agent is selected from at least one of talc and micronized silica gel.

6. The colon-targeted release formulation of estazolam according to claim 1, characterized in that, The positioning coating material is Euteqi S100 and pectin, with a mass ratio of (2~4):

1.

7. A method for preparing an estazolam colon-targeted release formulation, characterized in that, Includes the following steps: S1. Crush estazolam and sodium carboxymethyl starch through a 100-mesh sieve and mix them evenly; S2. Add binder solution to make soft material, granulate through 20 mesh sieve, dry at 50~60℃, and granulate through 18 mesh sieve; S3. Add the sieved lubricant and mix evenly, then compress to obtain a tablet core; in the tablet core, the mass ratio of estazolam to excipients is 1:(50~150), and the sodium carboxymethyl starch accounts for 3-8% of the tablet core mass; S4. Disperse the coating material, plasticizer, and anti-adhesion agent in a mixed solvent and stir until uniform to obtain a coating solution with a solid content of 5-12%. The mixed solvent is ethanol and water in a volume ratio of (2-4):

1. S5. Spray-coat the tablet cores, control the coating temperature at 35~45℃, increase the coating weight to 8~18%, and dry to obtain the colonic-targeted release formulation of estazolam.

8. The preparation method according to claim 7, characterized in that, During the coating process, the particle moisture content is controlled to be ≤3%; and / or, after coating, the particles are vacuum dried at 40°C for 4-6 hours to remove residual solvent.

9. The use of the colon-targeted release formulation of estazolam according to any one of claims 1 to 6, or the colon-targeted release formulation of estazolam prepared by the preparation method according to claim 7 or 8, in the preparation of drugs for treating neuropsychiatric and colon-related diseases.

10. The application according to claim 9, characterized in that, The conditions mentioned include anxiety disorders, insomnia, epilepsy, seizures, tension and fear, colonic neurological dysfunction, or intestinal spasms accompanied by anxiety.