Tolterodine sustained-release prescription composition

Abstract

The tolterodine sustained-release prescription composition comprises a core layer, an isolating layer, a sustained-release layer and an enteric-coated layer, the core layer is a sucrose pellet core, and the surface of the core layer is coated with tolterodine tartrate and hydroxypropyl methylcellulose; the isolation layer is made of hydroxypropyl methylcellulose, and the thickness of the isolation layer is 10-20 microns; the sustained-release layer is prepared from an ethyl cellulose aqueous dispersion and triethyl citrate, and silicon dioxide nanoparticles are added; and the enteric-coated layer is acrylic resin and is dissolved when the pH value is greater than or equal to 5.5. The accumulated dissolution rate of the composition in simulated gastric juice with a pH value of 1.2 within 2 hours is less than or equal to 10%, the accumulated dissolution rate in simulated intestinal juice with a pH value of 6.8 within 7 hours is more than or equal to 85%, and the accumulated dissolution rate in a buffer solution with a pH value of 4.5 within 3 hours is reduced by more than 20% compared with a reference preparation; through collaborative design of multiple layers of coatings, collaborative reinforcement of the plasticizer and the nanoparticles and introduction of the pH response type enteric-coated layer, the acid resistance, the release stability and the targeting property of the medicine are remarkably improved, the problems of burst release of gastric juice and unstable release of intestinal tracts of a traditional preparation are solved, and the preparation has outstanding clinical application value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly to a tolterodine sustained-release prescription composition. Background Art

[0002] Tolterodine is a commonly used drug for the treatment of overactive bladder (OAB), and its sustained-release preparation needs to achieve a stable release in the gastrointestinal tract to maintain long-term efficacy. However, the existing tolterodine sustained-release preparations have the following significant defects:

[0003] Problem of sudden release in gastric juice: Traditional sustained-release preparations mostly use a single coating layer or conventional sustained-release materials (such as hydroxypropyl methylcellulose), which are prone to sudden drug release in gastric juice (pH 1.2), resulting in gastric irritation and fluctuations in blood drug concentration, affecting patient compliance. For example, the dissolution rate of the reference preparation in the prior art in pH 1.2 simulated gastric juice reaches 20% in 2 hours, significantly increasing the risk of gastrointestinal adverse reactions.

[0004] Unstable release in the intestine: In the intestine (pH 6.8), due to insufficient mechanical strength of the coating layer or improper material selection in traditional preparations, the release rate is unstable, making it difficult to meet the stable release requirements of "≤15% in 1 hour, 40% - 60% in 3 hours, ≥85% in 7 hours".

[0005] Insufficient acid resistance: In a pH 4.5 buffer solution, the dissolution rate of existing preparations in 3 hours is relatively high (such as 63% for the reference preparation), which may lead to premature release of the drug in the acidic intestinal environment and reduce the efficacy.

[0006] Large batch-to-batch differences: Traditional coating processes (such as constant-temperature coating) are prone to surface cracks or internal stress concentration in the coating layer, resulting in differences in release behavior between batches (such as dissolution rate fluctuations > 10%), affecting the controllability of product quality. Summary of the Invention

[0007] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this part, as well as in the abstract and title of the present application, to avoid obscuring the purpose of this part, the abstract, and the title, but such simplifications or omissions cannot be used to limit the scope of the present invention.

[0008] To solve the problems of sudden release of tolterodine sustained-release preparations in gastric juice, unstable release in the intestine, and insufficient acid resistance in the prior art, the present invention provides a novel tolterodine sustained-release prescription composition; through the design of a multi-layer coating structure and material optimization, this composition realizes the precise release of the drug in different pH environments of the gastrointestinal tract, significantly improving the acid resistance, release stability, and targeting of the drug.

[0009] Specifically, the composition comprises the following components:

[0010] An isolation layer, made of an isolation layer material coated outside the drug-loading layer;

[0011] A sustained-release layer, made of a sustained-release layer material coated outside the isolation layer;

[0012] An enteric-coated layer, made of an enteric-coated layer material coated outside the sustained-release layer;

[0013] Wherein, the cumulative dissolution of the composition in simulated gastric fluid at pH 1.2 within 2 hours is ≤10%, and the cumulative dissolution in simulated intestinal fluid at pH 6.8 within 7 hours is ≥85%.

[0014] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the drug-loading layer material comprises hypromellose (HPMC K15M), and its dosage is 2.0% - 3.0% of the total mass of the composition.

[0015] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the isolation layer material comprises hypromellose, and its dosage is 8% - 12% of the total mass of the composition, and the thickness of the isolation layer is 10 - 20 μm.

[0016] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the sustained-release layer material comprises an ethylcellulose aqueous dispersion and a plasticizer. The dosage of the ethylcellulose aqueous dispersion is 18% - 22% of the total mass of the composition, and the plasticizer is triethyl citrate, and the mass ratio thereof to ethylcellulose is 1:5.

[0017] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the sustained-release layer material further contains silica nanoparticles, and its dosage is 0.1% - 0.5% of the total mass of the composition.

[0018] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the enteric-coated layer material comprises acrylic resin (Eudragit L100-55), and its dosage is 5% - 8% of the total mass of the composition, and it dissolves at pH ≥ 5.5.

[0019] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the dosage of the sucrose core is 50% - 60% of the total mass of the composition.

[0020] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the dosage of tolterodine tartrate is 1.5% - 3.0% of the total mass of the composition.

[0021] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the release behavior of the composition in pH 6.8 simulated intestinal fluid satisfies:

[0022] The cumulative dissolution at 1 hour ≤ 15%;

[0023] The cumulative dissolution at 3 hours is 40% - 60%;

[0024] The cumulative dissolution at 7 hours ≥ 85%.

[0025] As a preferred embodiment of the tolterodine sustained-release prescription composition of the present invention, wherein: the cumulative dissolution of the composition in pH 4.5 buffer solution at 3 hours is reduced by more than 20% compared with the reference preparation.

[0026] Advantages of the present invention:

[0027] 1. The present invention realizes precise release through the collaborative design of multi-layer coating; specifically, the sucrose pill core in the core layer serves as a drug carrier, and the surface is coated with tolterodine tartrate and hypromellose to ensure uniform distribution of the drug; the hypromellose in the isolation layer can effectively isolate the drug-loading layer and the sustained-release layer, preventing drug migration and interaction with the coating layer; the ethylcellulose aqueous dispersion and triethyl citrate in the sustained-release layer form a flexible coating film, combined with silicon dioxide nanoparticles, significantly improving the mechanical strength and moisture resistance, and achieving a stable release in pH 6.8 intestinal fluid; the acrylic resin in the enteric coating layer dissolves at pH ≥ 5.5, ensuring that the drug is hardly released in gastric juice and rapidly initiating targeted sustained release in the intestine; through the synergistic effect of the four-layer coating, the drug release behavior highly matches the pH environment of the gastrointestinal tract, solving the problems of sudden release in gastric juice and unstable release in the intestine of traditional preparations.

[0028] 2. The present invention adopts the synergistic strengthening mechanism of plasticizer and nanoparticles, significantly improving the mechanical properties and release controllability of the sustained-release layer, and being applicable to complex storage and transportation conditions; specifically, triethyl citrate is used as a plasticizer to form a dense and flexible coating film with ethylcellulose, reducing coating cracks; silicon dioxide nanoparticles are used as nano-fillers and uniformly dispersed in the sustained-release layer, enhancing the moisture resistance of the coating layer through physical cross-linking, ensuring the release stability under high temperature and high humidity environments.

[0029] 3. The acrylic resin in the present invention rapidly dissolves at pH ≥ 5.5, ensuring that the drug is only released in the intestine, effectively avoiding premature release in the acidic intestinal environment, significantly reducing gastric irritation, and improving drug safety and patient compliance. Description of the Drawings

[0030] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings. Among them:

[0031] Figure 1 It is the process flow chart for the preparation of the present invention. Specific embodiments

[0032] To make the above objects, features, and advantages of the present invention more obvious and understandable, the following will make a detailed description of the specific embodiments of the present invention in conjunction with the drawings of the specification.

[0033] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar generalizations without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0034] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that can be included in at least one implementation manner of the present invention. The "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor is it a separate or selectively exclusive embodiment from other embodiments.

[0035] Embodiment 1

[0036] This is the first embodiment of the present invention, which provides a tolterodine sustained-release prescription composition. The composition includes the following components and mass percentages:

[0037] Core layer: Sucrose core (50% - 60%), coated with a drug-loading layer of tolterodine tartrate (1.5% - 3.0%) and hypromellose (HPMC K15M, 2.0% - 3.0%); among them, the sucrose core in the core layer serves as the core, and the tolterodine tartrate and the drug-loading layer material (HPMC K15M) are coated on the surface to ensure uniform distribution of the drug.

[0038] Isolation layer: Hypromellose coated outside the drug-loading layer (isolation layer thickness 10 - 20 μm, 8% - 12%); among them, the use of hypromellose in the isolation layer can effectively isolate the drug-loading layer from the sustained-release layer and avoid drug migration during the coating process.

[0039] Sustained-release layer: It is composed of ethylcellulose aqueous dispersion (18% - 22%), triethyl citrate (ethylcellulose: plasticizer = 5:1, 4.5% - 5.5%), and silica nanoparticles (0.1% - 0.5%); among them, triethyl citrate is used as a plasticizer to form a flexible coating film with ethylcellulose, enhancing the mechanical strength of the sustained-release layer and reducing coating cracks; silica nanoparticles are used as nano-fillers and are uniformly dispersed in the sustained-release layer to further improve the moisture resistance and release stability of the coating layer; through the synergistic effect of ethylcellulose aqueous dispersion and triethyl citrate, combined with silica nanoparticles, the mechanical strength and release stability of the sustained-release layer are significantly improved, avoiding the release behavior fluctuations caused by humidity or temperature changes in traditional preparations, and being suitable for drug storage and transportation in high humidity or high temperature environments to ensure the stability of drug release behavior.

[0040] Enteric-coated layer: Acrylic resin (Eudragit L100 - 55, 5% - 8%) coated outside the sustained-release layer, which dissolves at pH ≥ 5.5, ensuring that the drug is hardly released in gastric juice, reducing gastric irritation, and quickly initiating sustained release in the intestine to enhance the targeting; in this embodiment, by introducing a pH-responsive enteric-coated layer, low release of the drug in gastric juice and targeted sustained release in the intestine are achieved, significantly improving the safety and efficacy of the drug, being suitable for drug preparations that need to be targeted and released in the intestine, reducing gastric irritation, and enhancing the therapeutic effect.

[0041] The total mass percentage of each layer is 100%.

[0042] The release behavior of the above composition satisfies:

[0043] Simulated gastric juice at pH 1.2: The cumulative dissolution rate within 2 hours ≤ 10%, significantly lower than 20% of traditional preparations;

[0044] Simulated intestinal fluid at pH 6.8: ≤ 15% within 1 hour, 40% - 60% within 3 hours, ≥ 85% within 7 hours, and the release curve is smoother;

[0045] Buffer solution at pH 4.5: The dissolution rate within 3 hours is reduced by more than 20% compared with the reference preparation, and the acid resistance is significantly improved.

[0046] The composition in this scheme realizes low release of the drug in gastric juice (pH 1.2, ≤ 10% within 2 hours) and stable release in the intestine (pH 6.8, ≥ 85% within 7 hours) through a multi-layer coating design, solves the problems of sudden release of traditional preparations in gastric juice and unstable release in the intestine, significantly improves the safety and efficacy of the drug, is suitable for the treatment of overactive bladder, reduces gastric irritation, and improves patient compliance.

[0047] The preparation method of the above-mentioned tolterodine sustained-release prescription composition includes the following steps:

[0048] Drug-loading layer coating: Tolterodine tartrate and HPMC K15M were mixed and dissolved in an ethanol-water (70:30) solution, and then coated on the surface of sucrose pellets by a fluidized bed coating process (temperature 35°C ± 2°C, flow rate 2 - 4 mL / min) to ensure uniform distribution of the drug.

[0049] Isolation layer coating: Hydroxypropyl methylcellulose (10% aqueous solution) was coated at a spraying rate of 1.5 - 2.5 g / min to form an isolation layer with a thickness of 15 ± 5 μm, effectively isolating the drug-loading layer from the sustained-release layer.

[0050] Sustained-release layer coating: An ethylcellulose aqueous dispersion (solid content 12% - 15%) was mixed with triethyl citrate and silicon dioxide nanoparticles, and coated with a gradient temperature increase (initial 30°C → final 45°C), controlling the coating weight gain to 20% - 25%. By adopting the gradient temperature increase coating process and combining plasticizers and nanoparticles, the mechanical properties and release stability of the sustained-release layer were significantly improved;

[0051] Enteric-coated layer coating: Eudragit L100-55 (15% ethanol solution) was coated at a flow rate of 1.0 - 1.5 mL / min (ensuring that the drug is hardly released in gastric juice and is targeted for sustained release in the intestine), and after drying, the sustained-release pellets were obtained and filled into hard capsule shells.

[0052] Through the systematic optimization of the multi-layer coating process, low release of the drug in gastric juice and targeted sustained release in the intestine were achieved, solving the problem of unstable release behavior of traditional preparations.

[0053] In the above steps, the gradient temperature increase coating is divided into three stages:

[0054] The first stage (30°C - 35°C): Coating rate 3 mL / min, forming a dense bottom layer structure to ensure the mechanical strength of the sustained-release layer and the stability of drug release;

[0055] The second stage (35°C - 40°C): Coating rate 2 mL / min, enhancing the uniformity of the sustained-release layer and avoiding stress concentration inside the coating layer;

[0056] The third stage (40°C - 45°C): Coating rate 1 mL / min, reducing surface cracks and improving the appearance quality of the coating layer and the stability of drug release.

[0057] By the gradient temperature increase coating process, the mechanical properties and release stability of the sustained-release layer were significantly improved, solving the problems of surface cracks and internal stress concentration in the coating layer in the traditional constant temperature process.

[0058] In this example, through the systematic optimization of the gradient temperature - rising coating process, the synergistic effect of plasticizers and nanoparticles, the pH - responsive enteric - soluble layer, and the multi - layer coating process, the acid resistance, release stability, and targeting of the tolterodine sustained - release prescription composition are significantly improved, solving the deficiencies of the prior art and having high clinical application value.

[0059] Example 2

[0060] As shown in the Figure 1 accompanying drawings, this is the second example of the present invention. The difference between this example and the first example is that in order to verify the technical advantages of this composition, experiments were conducted on the preparation of this composition. The specific experimental steps are as follows:

[0061] I. Experiment Preparation and Implementation Process

[0062] 1. Experiment preparation;

[0063] Prepare the following materials:

[0064] Sucrose pellets (core layer): 108.54 mg per pellet, accounting for 60.3% of the total mass;

[0065] Tolterodine tartrate (API): 4.0 mg per pellet, accounting for 2.2% of the total mass;

[0066] Hydroxypropyl methylcellulose (HPMC K15M, drug - loading layer): 4.5 mg per pellet, accounting for 2.5% of the total mass;

[0067] Hydroxypropyl methylcellulose (barrier layer): 18 mg per pellet, accounting for 10% of the total mass. The thickness of the barrier layer is controlled at 15 ± 5 μm;

[0068] Ethylcellulose aqueous dispersion (sustained - release layer): 36 mg per pellet, accounting for 20% of the total mass. The plasticizer is triethyl citrate (ethylcellulose: plasticizer = 5:1);

[0069] Silica nanoparticles (sustained - release layer): 0.18 mg per pellet, accounting for 0.1% of the total mass;

[0070] Acrylic resin (Eudragit L100 - 55, enteric - soluble layer): 9 mg per pellet, accounting for 5% of the total mass.

[0071] 2. Equipment preparation;

[0072] Fluidized - bed coater (for multi - layer coating process);

[0073] Dissolution tester (for measuring the drug release behavior);

[0074] High - performance liquid chromatograph (HPLC, for content determination and related substance detection).

[0075] 3. Implementation process:

[0076] Coating of the drug-loading layer:

[0077] Mix tolterodine tartrate with HPMC K15M and dissolve them in an ethanol-water (70:30) solution. Then, using the fluidized bed coating process, coat it on the surface of sucrose pellets. The coating temperature is 35°C ± 2°C, and the flow rate is 3 mL / min to ensure uniform distribution of the drug-loading layer.

[0078] Coating of the isolation layer:

[0079] Coat hydroxypropyl methylcellulose (10% aqueous solution) on the surface of the drug-loading layer at a spraying rate of 2.0 g / min to form an isolation layer with a thickness of 15 ± 5 μm, ensuring physical isolation between the drug-loading layer and the sustained-release layer.

[0080] Coating of the sustained-release layer:

[0081] Mix ethylcellulose aqueous dispersion with triethyl citrate and silicon dioxide nanoparticles, and use the gradient temperature-rising coating process (initial 30°C → final 45°C) to control the coating weight gain of 20% - 25% to ensure the mechanical strength and release stability of the sustained-release layer.

[0082] Coating of the enteric layer:

[0083] Coat Eudragit L100-55 (15% ethanol solution) on the surface of the sustained-release layer at a flow rate of 1.5 mL / min to ensure that the enteric layer dissolves at pH ≥ 5.5, achieving low release in gastric juice and targeted sustained release in the intestine.

[0084] Drying and filling:

[0085] Dry the coated pellets at 40°C for 2 hours and fill them into hard gelatin capsule shells to obtain the tolterodine sustained-release formulation composition.

[0086] Comparative test:

[0087] Reference preparation: A tolterodine sustained-release preparation with a traditional single coating layer design (without an enteric layer, and the sustained-release layer only contains ethylcellulose).

[0088] Test conditions: Conduct dissolution tests in pH 1.2 simulated gastric juice, pH 4.5 buffer solution, and pH 6.8 simulated intestinal fluid respectively, and record the cumulative dissolution data.

[0089] II. The comparative test data are shown in the following table;

[0090]

[0091]

[0092] III. Table Data Analysis;

[0093] 1. Acid Resistance in pH 1.2 Simulated Gastric Juice:

[0094] The cumulative dissolution rate of the self-developed preparation within 2 hours was only 5%, significantly lower than 20% of the reference preparation; by introducing an enteric coating layer (Eudragit L100-55), the self-developed preparation hardly released the drug in gastric juice, reducing gastric irritation and improving patient tolerance.

[0095] 2. Release Behavior in pH 4.5 Buffer:

[0096] The cumulative dissolution rate of the self-developed preparation within 3 hours was 58%, a 5% reduction compared to 63% of the reference preparation; by adding silica nanoparticles and optimizing the design of the sustained-release layer, the release curve of the self-developed preparation was smoother, avoiding the phenomenon of burst release and improving the stability of the drug in an acidic environment.

[0097] 3. Release Behavior in pH 6.8 Simulated Intestinal Fluid:

[0098] The cumulative dissolution rate of the self-developed preparation within 7 hours was 92%, comparable to that of the reference preparation, but the release rates at 1 hour and 3 hours were lower (12% vs 14% at 1 hour, 55% vs 66% at 3 hours); by means of a multi-layer coating design, the release of the self-developed preparation in the intestine was smoother, avoiding early burst release and improving the long-acting sustained-release effect of the drug.

[0099] In summary, the release behavior of the self-developed preparation of the present invention in media of pH 1.2, pH 4.5 and pH 6.8 is superior to that of the reference preparation, especially outstanding in terms of acid resistance and release smoothness; by introducing an enteric coating layer, optimizing the design of the sustained-release layer and adding nanoparticles, the release behavior of the self-developed preparation in multiple pH environments has been significantly improved, with non-obvious technical effects.

[0100] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A tolterodine sustained-release prescription composition, characterized in that: It comprises the following components: Core layer, sucrose pellet core, with tolterodine tartrate and drug-loading layer material coated on the surface; Isolation layer, isolation layer material coated outside the drug-loading layer; Sustained-release layer, sustained-release layer material coated outside the isolation layer; Enteric-soluble layer, enteric-soluble layer material coated outside the sustained-release layer; Among them, the cumulative dissolution rate of the composition in simulated gastric fluid at pH 1.2 for 2 hours is ≤10%, and the cumulative dissolution rate in simulated intestinal fluid at pH 6.8 for 7 hours is ≥85%.

2. The tolterodine sustained-release prescription composition according to claim 1, wherein: The drug-loading layer material includes hypromellose, and its dosage is 2.0% - 3.0% of the total mass of the composition.

3. The tolterodine sustained-release prescription composition according to claim 2, characterized in that: The isolation layer material includes hypromellose, and its dosage is 8% - 12% of the total mass of the composition, and the thickness of the isolation layer is 10 - 20 μm.

4. The tolterodine sustained-release pharmaceutical composition according to claim 3, characterized in that: The sustained-release layer material includes ethylcellulose aqueous dispersion and a plasticizer. Among them, the dosage of ethylcellulose aqueous dispersion is 18% - 22% of the total mass of the composition, and the plasticizer is triethyl citrate, and its mass ratio to ethylcellulose is 1:

5.

5. The tolterodine sustained-release prescription composition according to claim 4, characterized in that: The sustained-release layer material further contains silica nanoparticles, and its dosage is 0.1% - 0.5% of the total mass of the composition.

6. The tolterodine sustained-release prescription composition according to claim 5, wherein: The enteric-soluble layer material includes acrylic resin, and its dosage is 5% - 8% of the total mass of the composition, and it dissolves at pH ≥ 5.

5.

7. The tolterodine sustained-release pharmaceutical composition according to claim 6, characterized in that: The dosage of the sucrose pellet core is 50% - 60% of the total mass of the composition.

8. The tolterodine sustained-release prescription composition according to claim 7, characterized in that: The dosage of tolterodine tartrate is 1.5% - 3.0% of the total mass of the composition.

9. The tolterodine sustained-release prescription composition according to claim 8, characterized in that: The release behavior of the composition in simulated intestinal fluid at pH 6.8 satisfies: The cumulative dissolution rate in 1 hour is ≤15%; The cumulative dissolution rate in 3 hours is 40% - 60%; The cumulative dissolution rate in 7 hours is ≥85%.

10. The tolterodine sustained-release pharmaceutical composition according to claim 9, characterized in that: The cumulative dissolution rate of the composition in pH 4.5 buffer solution in 3 hours is reduced by more than 20% compared with the reference preparation.

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